ABSTRACT
The poorly understood factors governing the small molecule activation reactions mediated by diazaborinines have been computationally explored in detail using quantum chemical tools. To this end, the activation of E-H σ-bonds (E = H, C, Si, N, P, O, S) has been investigated. These reactions, which proceed in a concerted manner, are exergonic and, in general, associated with relatively low activation barriers. In addition, the barrier becomes lower for the E-H bonds involving the heavier element in the same group (ΔG≠ : C>Si; N>P; O>S). This reactivity trend together with the mode of action of the diazaborinine system are quantitatively analyzed by means of the activation strain model of reactivity in combination with the energy decomposition analysis method.
ABSTRACT
The potential application of η6 -metalated aryl iodides as organocatalyst has been explored by means of computational methods. It is found that the enhanced halogen bonding donor ability of these species, in comparison with their demetalated counterparts, translates into a significant acceleration of the Diels-Alder cycloaddition reaction involving cyclohexadiene and methyl vinyl ketone. The factors behind this acceleration, the endo-exo selectivity of the process and the influence of the nature of the transition metal fragment in the activity of these species are quantitatively explored in detail by means of the combination of the Activation Strain Model of reaction and the Energy Decomposition Analysis methods.
ABSTRACT
The poorly understood factors controlling the catalysis and selectivity in Lewis acid-promoted Diels-Alder cycloaddition reactions involving vinylazaarenes as dienophiles have been quantitatively explored in detail by means of computational methods. With the help of the activation strain model and the energy decomposition analysis methods, it is found that the remarkable acceleration induced by the catalysis is mainly due to a significant reduction of the Pauli repulsion between the key occupied π-molecular orbitals of the reactants and not due to the proposed stabilization of the lowest unoccupied molecular orbital (LUMO) of the dienophile. This computational approach has also been helpful to understand the reasons behind the extraordinary regio- and diastereoselectivity observed experimentally. The insight gained in this work allows us to predict even more reactive vinylazaarene dienophiles, which may be useful in organic synthesis.
ABSTRACT
Lung cancer is the second cause of cancer related deaths worldwide. Chemotherapy and immunotherapy represent the current standard of care for advanced NSCLC. Platinum-based chemotherapy expands late-differentiated T cell populations. Therefore, immune restoration after chemotherapy to adjuvate the immunotherapeutic potential could be crucial. The aim of this study was to evaluate the effect of Biomodulina T (BT), a thymic polypeptide fraction, on peripheral lymphocytes subpopulations in the context of cancer disease. Additionally, whether these effects might induce a better response to CIMAvax-EGF, an epidermal growth factor (EGF) depleting immunotherapy. Eighteen advanced NSCLC patients were evaluated after being treated with platinum-based chemotherapy. We found that the frequency of terminally differentiated effector T cells re-expressing CD45RA (EMRA) CD4+ (p=0.0031) and CD8+ (p=0.0372) T cells decreased with the administration of BT, whereas CD4+ naive T cells increase in more than 70% of the patients. Remarkably, CD4+ and CD8+ T lymphocytes expressing programmed cell death receptor-1 (PD1) significantly decreased after BT administration (p=0.0005 and p<0.0001, respectively). We also found an enhancement of the anti-EGF antibody response with a large percentage of patients treated with CIMAvax-EGF reaching the good antibody response condition after four vaccine doses. Moreover, the median overall survival of patients treated with CIMAvax-EGF was 16.09 months. In conclusion, our results suggest that the immunorestoration generated by the administration of BT after first-line chemotherapy may induce a better immune response to CIMAvax-EGF that could translate into the clinical benefit of patients diagnosed with advanced NSCLC.
ABSTRACT
The factors responsible for the enhancement of the halogen bond by an adjacent hydrogen bond have been quantitatively explored by means of state-of-the-art computational methods. It is found that the strength of a halogen bond is enhanced by ca. 3 kcal/mol when the halogen donor simultaneously operates as a halogen bond donor and a hydrogen bond acceptor. This enhancement is the result of both stronger electrostatic and orbital interactions between the XB donor and the XB acceptor, which indicates a significant degree of covalency in these halogen bonds. In addition, the halogen bond strength can be easily tuned by modifying the electron density of the aryl group of the XB donor as well as the acidity of the hydrogen atoms responsible for the hydrogen bond.
ABSTRACT
The poorly understood mode of activation and catalysis of bidentate iodine(III)-based halogen donors have been quantitatively explored in detail by means of state-of-the-art computational methods. To this end, the uncatalyzed Diels-Alder cycloaddition reaction between cyclohexadiene and methyl vinyl ketone is compared to the analogous process mediated by a bidentate iodine(III)-organocatalyst and by related, highly active iodine(I) species. It is found that the bidentate iodine(III)-catalyst accelerates the cycloaddition by lowering the reaction barrier up to 10 kcal mol-1 compared to the parent uncatalyzed reaction. Our quantitative analyses reveal that the origin of the catalysis is found in a significant reduction of the steric (Pauli) repulsion between the diene and dienophile, which originates from both a more asynchronous reaction mode and a significant polarization of the π-system of the dienophile away from the incoming diene. Notably, the activity of the iodine(III)-catalyst can be further enhanced by increasing the electrophilic nature of the system. Thus, novel systems are designed whose activity actually surpasses that of strong Lewis acids such as BF3.
ABSTRACT
RESEARCH QUESTION: Does clinical performance of personalized embryo transfer (PET) guided by endometrial receptivity analysis (ERA) differ from frozen embryo transfer (FET) or fresh embryo transfer in infertile patients undergoing IVF? DESIGN: Multicentre, open-label randomized controlled trial; 458 patients aged 37 years or younger undergoing IVF with blastocyst transfer at first appointment were randomized to PET guided by ERA, FET or fresh embryo transfer in 16 reproductive clinics. RESULTS: Clinical outcomes by intention-to-treat analysis were comparable, but cumulative pregnancy rate was significantly higher in the PET (93.6%) compared with FET (79.7%) (Pâ¯=â¯0.0005) and fresh embryo transfer groups (80.7%) (Pâ¯=â¯0.0013). Analysis per protocol demonstrates that live birth rates at first embryo transfer were 56.2% in PET versus 42.4% in FET (Pâ¯=â¯0.09), and 45.7% in fresh embryo transfer groups (Pâ¯=â¯0.17). Cumulative live birth rates after 12 months were 71.2% in PET versus 55.4% in FET (Pâ¯=â¯0.04), and 48.9% in fresh embryo transfer (Pâ¯=â¯0.003). Pregnancy rates at the first embryo transfer in PET, FET and fresh embryo transfer arms were 72.5% versus 54.3% (Pâ¯=â¯0.01) and 58.5% (Pâ¯=â¯0.05), respectively. Implantation rates at first embryo transfer were 57.3% versus 43.2% (Pâ¯=â¯0.03), and 38.6% (Pâ¯=â¯0.004), respectively. Obstetrical outcomes, type of delivery and neonatal outcomes were similar in all groups. CONCLUSIONS: Despite 50% of patients dropping out compared with 30% initially planned, per protocol analysis demonstrates statistically significant improvement in pregnancy, implantation and cumulative live birth rates in PET compared with FET and fresh embryo transfer arms, indicating the potential utility of PET guided by the ERA test at the first appointment.
Subject(s)
Embryo Transfer/methods , Fertilization in Vitro/methods , Infertility, Female/therapy , Adult , Birth Rate , Cryopreservation , Female , Humans , Live Birth , Pregnancy , Pregnancy Rate , Treatment OutcomeABSTRACT
OBJECTIVE: To study reproductive outcome in patients cured of cancer who required oocyte donation (OD) owing to iatrogenic ovarian dysfunction. DESIGN: Multicenter, unmatched, retrospective cohorts study. SETTING: Private, university-affiliated group of clinics. PATIENT(S): Women treated and cured of cancer (n = 142) who underwent 333 cycles of OD (exposed group) and women without a previous cancer diagnosis (n = 17,844) who underwent 29,778 cycles of OD (unexposed cohort) between January 2000 and January 2012. INTERVENTION(S): Retrospective chart review. MAIN OUTCOME MEASURE(S): Pregnancy, implantation, miscarriage, and ongoing pregnancy rates. RESULT(S): There were no differences in terms of pregnancy (55.7% vs. 54.7%), implantation (39.8% vs. 38.2%), miscarriage (29.5% vs. 26.9%), or delivery rates (39.3% vs. 39.9%) between the unexposed group and the patients previously diagnosed and cured of cancer, respectively. There was no correlation between OD outcome and cancer type. CONCLUSION(S): Endometrial receptivity in women treated and cured of cancer was comparable to that of general patients without previous malignancies who had received OD, based on the largest series available in the literature.
Subject(s)
Abortion, Spontaneous/epidemiology , Infertility, Female/epidemiology , Infertility, Female/therapy , Neoplasms/epidemiology , Oocyte Donation/statistics & numerical data , Ovarian Diseases/epidemiology , Pregnancy Outcome/epidemiology , Adult , Causality , Cohort Studies , Female , Humans , Incidence , Ovarian Diseases/therapy , Pregnancy , Pregnancy Rate , Retrospective Studies , Risk Factors , Spain/epidemiology , Survivors/statistics & numerical data , Treatment OutcomeABSTRACT
AIMS: Fucosylation is regulated by fucosyltransferases, the guanosine diphosphate-L-fucose (GDP-L-Fuc) synthetic pathway, and the GDP-L-fucose transporter (GDP-L-Fuc Tr). We have reported previously an increased level of α(1,6)fucosyltransferase activity and expression in colorectal cancer (CRC). The present study aimed to analyse the expression profiles of the FX enzyme and GDP-L-Fuc Tr in a cohort of operated CRC patients to elucidate their role in α(1,6)fucosylation in this neoplasm. METHODS AND RESULTS: We assessed the immunohistochemical expression of FX and GDP-L-Fuc Tr in a series of tumour samples and healthy tissues from CRC specimens. FX expression was observed in 58 of 91 (63.7%) tumours and 23 of 28 (82.1%) corresponding healthy samples. GDP-L-Fuc Tr expression was detected in 86 of 102 (84.3%) colorectal tumours, and 13 of 27 (48.1%) healthy tissue specimens. The expression of GDP-L-Fuc Tr was statistically higher in tumours than in healthy tissues (P < 0.001). A correlation was found between FX and GDP-L-Fuc Tr expression in tumour samples (P = 0.003). CONCLUSION: GDP-L-Fuc Tr overexpression in the tumour tissue of CRC patients suggests that GDP-L-Fuc transport to the Golgi apparatus may be an important factor associated with increased α(1,6)fucosylation in CRC.
Subject(s)
Carbohydrate Epimerases/metabolism , Colorectal Neoplasms/metabolism , Fucosyltransferases/metabolism , Guanosine Diphosphate Fucose/metabolism , Ketone Oxidoreductases/metabolism , Monosaccharide Transport Proteins/metabolism , Aged , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Glycosylation , Golgi Apparatus/metabolism , Humans , Hydro-Lyases/metabolism , Immunohistochemistry , Male , PrognosisABSTRACT
Abnormal luteal function is a common issue in assisted reproduction techniques associated with ovarian stimulation probably due to low levels of LH in the middle and in the late luteal phase. This defect seems to be associated with supraphysiological steroid levels at the end of follicular phase. The luteal phase insufficiency has not got a diagnostic test which has proven reliable in a clinical setting. Luteal phase after ovarian stimulation becomes shorter and insufficient, resulting in lower pregnancy rates. Luteal phase support with progesterone or hCG improves pregnancy outcomes and no differences are found among different routes of administration. However, hCG increases the risk of ovarian hyperstimulation syndrome. In relation to the length of luteal support, the day of starting it remains controversial and it does not seem necessary to continue once a pregnancy has been established. After GnRHa triggering ovulation, intensive luteal support or hCG bolus can overcome the defect in luteal phase, but more studies are needed to show the LH utility as support.
Subject(s)
Fertilization in Vitro , Infertility, Female/drug therapy , Luteal Phase/physiology , Ovarian Hyperstimulation Syndrome/drug therapy , Ovulation/drug effects , Pregnancy Rate , Chorionic Gonadotropin/administration & dosage , Chorionic Gonadotropin/therapeutic use , Estradiol/therapeutic use , Female , Gonadotropin-Releasing Hormone/administration & dosage , Gonadotropin-Releasing Hormone/agonists , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/therapeutic use , Humans , Luteal Phase/drug effects , Ovulation Induction , Pregnancy , Progesterone/administration & dosage , Progesterone/therapeutic useABSTRACT
LH is a glycoprotein that plays a crucial role in folliculogenesis during the natural ovarian cycles. It has the same activity and shares receptors with hCG. However the use of LH in combination with FSH in controlled ovarian stimulation remains controversial. A practical approach concerning the usefulness of LH according to the endogenous level of LH is described herein. Specific groups of patients can benefit from ovarian stimulation with LH. New applications of LH/hCG activity are also discussed.
Subject(s)
Luteinizing Hormone/pharmacology , Ovulation Induction/methods , Chorionic Gonadotropin/pharmacology , Female , Humans , Menstrual Cycle/drug effectsABSTRACT
BACKGROUND: A universal hallmark of cancer cells is the change in their glycosylation phenotype. One of the most frequent alterations in the normal glycosylation pattern observed during carcinogenesis is the enhancement of α(1,6)linked fucose residues of glycoproteins, due to the up-regulation of the α(1,6)fucosyltransferase activity. Our previous results demonstrated the specific alteration of this enzyme activity and expression in colorectal cancer, suggesting its implication in tumour development and progression. METHODS: In the current work we combined a LCA-affinity chromatography with SDS-PAGE and mass spectrometry in order to identify α(1,6)fucosylated proteins differentially expressed in colorectal cancer. This strategy allowed the identification of a group of α(1,6)fucosylated proteins candidates to be involved in CRC malignancy. RESULTS: The majority of the identified proteins take part in cell signaling and interaction processes as well as in modulation of the immunological response. Likewise, we confirmed the increased expression of GRP94 in colorectal cancer tissue and the significant down-regulation of the IgGFcBP expression in tumour cells. CONCLUSION: All these results validate the importance of core-fucosylated proteins profile analysis to understand the mechanisms which promote cancer onset and progression and to discover new tumour markers or therapeutic targets.
Subject(s)
Biomarkers, Tumor/metabolism , Colorectal Neoplasms/metabolism , Glycoproteins/metabolism , Blotting, Western , Chromatography, Affinity , Colorectal Neoplasms/diagnosis , Electrophoresis/methods , Fucose/metabolism , Glycosylation , Humans , Immunohistochemistry , Mass Spectrometry , Protein Isoforms/metabolismABSTRACT
OBJECTIVE: CDw75 is an α(2,6)-sialylated antigen associated with a poor prognosis in gastric cancer. In the present study, we examined if CDw75 expression in colorectal cancer (CRC) predicts tumour recurrence. Besides, we evaluated CDw75 expression in different colorectal tissue specimens to clarify their role in tumour development and progression. METHODS: We analyzed CDw75 expression in 34 specimens of healthy disease-free colorectal mucosa, 19 specimens of inflammatory colorectal mucosa, 73 colorectal adenomas, 35 specimens of healthy tissue and 101 specimens of tumoural tissue from CRC patients. RESULTS: None of the healthy disease-free and inflammatory colorectal mucosa specimens showed the presence of the epitope. CDw75 was expressed in 26% of the colorectal adenomas. In healthy and tumoural tissue from CRC patients, CDw75 was detected in 22.9% and 82.2% of the specimens, respectively. CDw75 expression in tumoural tissue was correlated with growth pattern (p = 0.044), Dukes stage (p = 0.002), TNM stage (p = 0.020) and distant metastasis (p = 0.005). Survival analysis showed that CDw75 expression is not associated with tumour recurrence. CONCLUSION: CDw75 expression in CRC is not a prognostic factor for predicting disease-free survival. Nevertheless, CDw75 expression may be a good marker of tumour progression and of the malignant potential of CRC.
Subject(s)
Antigens, CD/metabolism , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Sialyltransferases/metabolism , Adenocarcinoma/enzymology , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adenocarcinoma/secondary , Adenoma/enzymology , Adenoma/immunology , Adenoma/pathology , Aged , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/enzymology , Disease Progression , Disease-Free Survival , Female , Humans , Immunohistochemistry , Intestinal Mucosa/enzymology , Intestinal Mucosa/immunology , Male , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/pathologyABSTRACT
BACKGROUND: Increased ST6Gal I activity has been associated with the alpha(2,6)sialylation enhancement of membrane glycoconjugates observed in metastatic colorectal carcinomas (CRC). Siaalpha(2,6)Galbeta(1,4)GlcNAc sequence, known as CDw75, is a sialylated carbohydrate determinant generated by the ST6Gal I. This epitope has been reported to be associated with the progression of gastric and colorectal tumours, hence there are only a few conclusive studies to date. METHODS: By radioisotopic techniques we evaluated the ST6Gal I activity in healthy, transitional and tumour tissues from 43 patients with CRC. By immunohistochemistry we assessed the CDw75 expression in 25 colorectal adenomas, 43 tumours, 13 transitional and 28 healthy tissues of CRC patients. RESULTS: ST6Gal I activity was likewise found to be statistically higher in tumour tissue respect to healthy tissue from CRC patients. CDw75 expression was positive in 20% of colorectal adenomas. Furthermore, 70% of tumour specimens and 8.3% of transitional specimens were positive for CDw75 expression, whereas none of the healthy ones showed the presence of the epitope. CONCLUSION: The major contribution of this study is the inclusion of data from transitional tissue and the analysis of CDw75 antigen expression in CRC and in colorectal adenomas, little known so far. ST6Gal I activity and CDw75 antigen expression were increased in CRC. Although their comparison did not reach the statistical significance, a great extent of patients showed both, an enhanced tumour ST6Gal I activity and an increased CDw75 expression in the tumour tissue. So, these two variables may play a role in malignant transformation. The expression of CDw75 in colorectal adenomas suggests that this antigen may be a tumour marker in CRC.
Subject(s)
Adenocarcinoma/metabolism , Adenoma/metabolism , Antigens, CD/biosynthesis , Antigens, CD/metabolism , Biomarkers, Tumor/analysis , Colorectal Neoplasms/metabolism , Sialyltransferases/biosynthesis , Sialyltransferases/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenoma/genetics , Adenoma/pathology , Aged , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Progression , Gene Expression , Humans , Immunohistochemistry , Neoplasm StagingABSTRACT
Changes in enzyme activity and the expression levels of alpha(1,6)fucosyltransferase [alpha(1,6)FT] have been reported in certain types of malignant transformations. To develop a better understanding of the role of alpha(1,6)FT in human colorectal carcinoma (CRC), we analysed the enzyme activity in healthy and tumour tissues. alpha(1,6)FT activity was considerably higher in tumour tissue than in healthy tissue and was related to gender, lymph node metastasis, type of growth and tumour stage. We also observed a significant increase in the alpha(1,6)FT expression in tumour tissues as compared to healthy and transitional tissues, inflammatory lesions and adenomas. The immunohistochemical expression in tumour tissues was correlated with the degree of infiltration through the intestinal wall. Finally, a statistical correlation was found between enzyme activity and expression obtained by Western blot in colorectal tumours when compared in the same patient. All these findings demonstrate an alteration of alpha(1,6)FT activity and expression in CRC.