Diffuse large B-cell lymphoma (DLBCL) has been shown to be comprised of at least two prognostic entities, depending on its resemblance to normal germinal center or activated B cells, using global ...gene expression profiling. Also, the expression patterns of bcl-6, CD10 and IRF-4 (also known as MUM1) have been suggested as alternative means of identifying the germinal- and nongerminal center (activated B-cell like) groups. In the present study, we evaluated by immunohistochemistry the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 in a large material of 161 DLBCL patients. Using two different approaches, patients with germinal center phenotype displayed a significantly better survival than the nongerminal center group. Positive staining for bcl-6 or CD10 predicted for superior survival, while expression of IRF-4 alone showed no association with prognosis. Furthermore, expression of bcl-2 was associated with worse event-free survival and overall survival. In a multivariate analysis, a high international prognostic index score (3–5), non-GC phenotype and bcl-2 were independent adverse prognostic factors. Here we confirm the prognostic importance of determining the germinal- or nongerminal center phenotype in patients with DLBCL.
The photochemical reactions performed by transition metal complexes have been proposed as viable routes towards solar energy conversion and storage into other forms that can be conveniently used in ...our everyday applications. In order to develop efficient materials, it is necessary to identify, characterize and optimize the elementary steps of the entire process on the atomic scale. To this end, we have studied the photoinduced electronic and structural dynamics in two heterobimetallic ruthenium-cobalt dyads, which belong to the large family of donor-bridge-acceptor systems. Using a combination of ultrafast optical and X-ray absorption spectroscopies, we can clock the light-driven electron transfer processes with element and spin sensitivity. In addition, the changes in local structure around the two metal centers are monitored. These experiments show that the nature of the connecting bridge is decisive for controlling the forward and the backward electron transfer rates, a result supported by quantum chemistry calculations. More generally, this work illustrates how ultrafast optical and X-ray techniques can disentangle the influence of spin, electronic and nuclear factors on the intramolecular electron transfer process. Finally, some implications for further improving the design of bridged sensitizer-catalysts utilizing the presented methodology are outlined.
The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common ...cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = -0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.
Premenstrual dysphoric disorder (PMDD) is characterized by depression, anxiety and other affective symptoms which recur in the luteal phase of the menstrual cycle. Evidence from animal models of ...depression and anxiety indicate the importance of neuroactive steroid hormones and the GABA(A) receptor in the etiology and potential treatment of mood disorders. These data are reviewed in the light of human clinical studies and specific animal models of PMDD.
To quantify cardiovascular health (CVH), the American Heart Association (AHA) recently launched an updated construct of the "Life's Simple 7" (LS7) score, the "Life's Essential 8" (LE8) score. This ...study aims to analyse the association between both CVH scores and carotid artery plaques and to compare the predictive capacity of such scores for carotid plaques.
Randomly recruited participants aged 50-64 years from the Swedish CArdioPulmonary bioImage Study (SCAPIS) were analysed. According to the AHA definitions, two CVH scores were calculated: i) the LE8 score (0, worst CVH; 100, best CVH) and two different versions of the LS7 score (0-7) and (0-14), 0 indicating the worst CVH. Ultrasound-diagnosed carotid plaques were classified as no plaque, unilateral, and bilateral plaques. Associations were studied by adjusted multinomial logistic regression models and adjusted (marginal) prevalences, while comparison between LE8 and LS7 scores was performed through receiver operating characteristic (ROC) curves.
After exclusions, 28,870 participants remained for analysis (50.3% women). The odds for bilateral carotid plaques were almost five times higher in the lowest LE8 (<50 points) group OR: 4.93, (95% CI: 4.19-5.79); adjusted prevalence 40.5%, (95% CI: 37.9-43.2) compared to the highest LE8 (≥80 points) group adjusted prevalence 17.2%, (95% CI: 16.2-18.1). Also, the odds for unilateral carotid plaques were more than two times higher in the lowest LE8 group OR: 2.14, (95% CI: 1.82-2.51); adjusted prevalence 31.5%, (95% CI: 28.9-34.2) compared to the highest LE8 group adjusted prevalence 29.4%, (95% CI: 28.3-30.5). The areas under ROC curves were similar between LE8 and LS7 (0-14) scores: for bilateral carotid plaques, 0.622 (95% CI: 0.614-0.630) vs. 0.621 (95% CI: 0.613-0.628),
= 0.578, respectively; and for any carotid plaque, 0.602 (95% CI: 0.596-0.609) vs. 0.600 (95% CI: 0.593-0.607),
= 0.194, respectively.
The new LE8 score showed inverse and dose-response associations with carotid plaques, particularly bilateral plaques. The LE8 did not outperform the conventional LS7 score, which showed similar ability to predict carotid plaques, especially when scored as 0-14 points. We conclude that both the LE8 and LS7 may be useful in clinical practice for monitoring CVH status in the adult population.
PEGylation is the most widely used method to chemically modify protein biopharmaceuticals, but surprisingly limited public data is available on the biophysical effects of protein PEGylation. Here we ...report the first large-scale study, with site-specific mono-PEGylation of 15 different proteins and characterization of 61 entities in total using a common set of analytical methods. Predictions of molecular size were typically accurate in comparison with actual size determined by size-exclusion chromatography (SEC) or dynamic light scattering (DLS). In contrast, there was no universal trend regarding the effect of PEGylation on the thermal stability of a protein based on data generated by circular dichroism (CD), differential scanning calorimetry (DSC), or differential scanning fluorimetry (DSF). In addition, DSF was validated as a fast and inexpensive screening method for thermal unfolding studies of PEGylated proteins. Multivariate data analysis revealed clear trends in biophysical properties upon PEGylation for a subset of proteins, although no universal trends were found. Taken together, these findings are important in the consideration of biophysical methods and evaluation of second-generation biopharmaceutical drug candidates.
Objective The effect of combined oral contraceptives (COCs) on female sexuality has long been a matter of discussion, but placebo-controlled studies are lacking. Thus, the aim of the present study ...was to investigate if an oestradiol-containing COC influences sexual function. Design Investigator-initiated, randomised, double-blinded, placebo-controlled clinical trial where 202 healthy women were randomised to a combined oral contraceptive (1.5 mg oestradiol and 2.5 mg nomegestrol acetate) or placebo for three treatment cycles. Methods Sexual function at baseline and during the last week of the final treatment cycle was evaluated by the McCoy Female Sexuality Questionnaire. Serum and hair testosterone levels were assessed at the same time points. Results Compared to placebo, COC use was associated with a small decrease in sexual interest (COC median change score: −2.0; interquartile range (IQR): −5.0 to 0.5 vs placebo: −1.0; IQR: −3.0 to 2.0, P = 0.019), which remained following adjustment for change in self-rated depressive symptoms (B = −0.80 ± 0.30, Wald = 7.08, P = 0.008). However, the proportion of women who reported a clinically relevant deterioration in sexual interest did not differ between COC or placebo users (COC 18 (22.2%) vs placebo 16 (17.8%), P = 0.47). Change in other measured aspects of sexual function as well as total score of sexual function did not differ between the two treatments. Conclusions This study suggests that use of oestradiol-based COCs is associated with reduced sexual interest. However, the changes are minute, and probably not of clinical relevance.
To validate human neural precursor cells (NPCs) as potential donor cells for transplantation therapy after spinal cord injury (SCI), we investigated the effect of NPCs, transplanted as neurospheres, ...in two different rat SCI models.
Human spinal cord-derived NPCs (SC-NPCs) transplanted 9days after spinal contusion injury enhanced hindlimb recovery, assessed by the BBB locomotor test. In spinal compression injuries, SC-NPCs transplanted immediately or after 1week, but not 7weeks after injury, significantly improved hindlimb recovery compared to controls. We could not detect signs of mechanical allodynia in transplanted rats.
Four months after transplantation, we found more human cells in the host spinal cord than were transplanted, irrespective of the time of transplantation. There was no focal tumor growth. In all groups the vast majority of NPCs differentiated into astrocytes.
Importantly, the number of surviving rat spinal cord neurons was highest in groups transplanted acutely and subacutely, which also showed the best hindlimb function. This suggests that transplanted SC-NPCs improve the functional outcome by a neuroprotective effect.
We conclude that SC-NPCs reliably enhance the functional outcome after SCI if transplanted acutely or subacutely, without causing allodynia. This therapeutic effect is mainly the consequence of a neuroprotective effect of the SC-NPCs.
•We studied if human neural precursor cells (hNPCs) improve outcome of spinal cord.•We used two different animal models of spinal cord injury (SCI).•Transplantation to acute and subacute (≤9days) injuries enhanced functional recovery.•Enhanced recovery correlated with increased survival of host spinal neurons.•Spinal cord-derived hNPCs should be considered for clinical trials in SCI.
Idiopathic recurrent miscarriage, defined as three or more consecutive miscarriages, is a distressing early pregnancy complication. Although, the etiology of recurrent miscarriage is still unknown, ...an aberrant regulation of the endometrial receptivity marker hyaluronan-binding protein 2 (HABP2) has been suggested. The objective of the present study was to investigate the effect of genetic variations of HABP2 in women with idiopathic recurrent miscarriage compared to fertile women.
This study was designed as a case-control study. In total, 165 women who had three or more consecutive miscarriages and 289 fertile women were included in the study. Polymorphisms in the HABP2 gene were analyzed using TaqMan SNP Genotyping Assays. Three polymorphisms in the HABP2 gene, rs1157916, rs2240879 and rs7080536 (Marburg I) were studied.
Polymorphism in HABP2 showed no significant difference in women with recurrent miscarriage compared to fertile women, except for rs1157916 minor A allele that was more prevalent among RM patients (p = 0.058). Significantly higher live birth rate was observed among women with three to four miscarriages compared to those with more miscarriages (p = 0.001).
Variations in the HABP2 gene did not seem to be involved in the etiology of recurrent miscarriage, while, the number of previous miscarriages had an impact on the live birth rate.
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