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With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin ...D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Ramstedt pyloromyotomy through a right upper quadrant (RUQ) transverse incision has been the traditional treatment for hypertrophic pyloric stenosis. Recently, laparoscopic (LAP) and circumumbilical ...(UMB) approaches have been introduced as alternative methods to improve cosmesis, but concerns about greater operative times, costs, and complications remain. This study compares the three operative techniques and examines their advantages and complication rates.
We performed a retrospective review of patients undergoing pyloromyotomy at a children’s hospital between January 1997 and June 2003.
Two hundred ninety patients underwent pyloromyotomy by LAP (n = 51), RUQ (n = 190), or UMB (n = 49). Complication rate, time to ad libitum feeding, incidence of emesis, and postoperative length of stay did not differ considerably among groups. Two LAP patients were converted to RUQ. Mucosal perforation occurred in three patients each in the RUQ and UMB groups, but none in the LAP group. Operative times were considerably less for LAP (25 ± 9 minutes) than for RUQ (32 ± 9 minutes) and UMB (42 ± 12 minutes) (p < 0.05, ANOVA, Bonferroni). Charges related to operations and anesthesia were considerably greater for UMB (operation: $1,574 ± $433; anesthesia: $731 ± $190) compared with the other two groups (p < 0.05, ANOVA, Bonferroni), but did not differ between LAP (operation: $1,299 ± $311; anesthesia: $586 ± $137) and RUQ (operation: $1,237 ± $411; anesthesia: $578 ± $167). Data are presented as mean ± SD.
Advantages of LAP include a shorter mean operative time without higher complications or costs. UMB is associated with the greatest mean operative time and costs. Laparoscopic pyloromyotomy is a safe and effective approach to the treatment of hypertrophic pyloric stenosis.
Abstract Aims Case payment mechanisms have become the principal means of remunerating hospitals in most developed countries. The purpose of this study was to make an international comparison of ...reimbursement for breast reconstructive surgery. Methods We analysed remuneration for unilateral and bilateral female breast reconstruction (pedicled flaps, free flaps, alloplastic procedures) across five different European countries. National grouper software was used to identify Diagnosis Related Groups from which the proceeds were derived. Results The mean reimbursement was € 5593 for pedicled flaps, € 9149 for free flaps and € 4037 for implant-based reconstructions. The highest payments were in Sweden and the lowest in Italy. When adjusting payments by purchasing power parities, the relation among the countries did not change. The Austrian system makes a clear distinction between one-stage and two-stage delayed reconstructive interventions whereas reimbursement in other countries favoured a two-stage approach. Only one of five national reimbursement systems distinguishes between unilateral and bilateral reconstructions. Conclusions Across a spectrum of European countries, reimbursement for breast reconstruction was based on similar procedure-specific systems, although there was a wide variation in tariffs and consideration of other factors such as underlying diagnosis. As delivery of healthcare becomes more rationalised, there is a need for individualised reimbursement which correlates directly with activity. Drawing on the experience of different healthcare systems may lead to development of a more robust and fair system of reimbursement.
Features of Isoforms of Human Soluble TACI Fichtner, Miriam L; Rübsamen, Heike; Smolle, Michaela ...
The Journal of immunology (1950),
07/2023, Letnik:
211, Številka:
2
Journal Article
Recenzirano
The BAFF/APRIL-system with the two cytokines BAFF and APRIL and their three receptors, transmembrane activator and CAML interactor (TACI), BAFF receptor, and B-cell maturation Ag, is important for B ...cell maintenance. The BAFF/APRIL system is a therapeutic target in B cell-derived malignancies and autoimmune diseases. However, unexpected outcomes of clinical trials with atacicept (TACI-Fc) underline our incomplete understanding of this system. Shedding of the three receptors is one important regulatory element. In humans, TACI exists in two isoforms generated through alternative splicing in their extracellular portion: TACI-long (l) has two cysteine-rich domains, whereas TACI-short (s) lacks the first low-affinity one. In this study, we discriminated soluble (s) forms of TACI-l and TACI-s with newly generated mAbs and found that both were spontaneously released from activated human B cells, with a predominance of sTACI-l. Furthermore, sTACI-l was also the dominant isoform in human serum. Vaccination with the mRNA vaccine from BioNTech does not significantly affect the serum levels of sTACI-l. Both TACI-s and TACI-l were shed by a disintegrin and metalloproteinase domain-containing protein 10. TACI-l and TACI-s formed homo- and hetero-oligomers in soluble and membrane-bound forms. Both sTACI-l and sTACI-s acted as decoy receptors for BAFF, but only sTACI-l also efficiently inhibited APRIL. Dimerization of sTACI-l enhanced its decoy functions only slightly. Together, we extend our knowledge of the complexity of the BAFF/APRIL system by identifying and characterizing the two soluble isoforms of TACI.
The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also ...the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.
The denudation of landscapes is affected by temporal and spatial variations in tectonics, climate, and vegetation. However, deciphering the contributions of these different processes has proven ...challenging. In this study, cosmogenic nuclide-derived modern and paleo catchment-wide denudation rates in four European rivers are investigated. We present 12 new and 4 recalculated cosmogenic nuclide-derived denudation rates from modern river sediments and 14 paleo-denudation rates from terraces deposited over the last 2 Ma. The catchments studied are located in regions with minimal Quaternary tectonic activity and span different climates over 12o latitude. Results indicate that modern denudation rates range between 16 ±11 and 51 ±7 mm/ka with no clear latitudinal variation. Modern denudation rates are compared with catchment geomorphic indices including slope, fluvial steepness index, and relief. The denudation rates correlate better to catchment topographic indices (R2 ≈ 0.4) rather than climate. Paleo-denudation rates range from 8 ±7 to 56 ±7 mm/ka and are associated with a possible increase in the average paleo-denudation rates over the past 2 Ma. Taken together, the results indicate that quantification of catchment-wide denudation rates over long (Quaternary) time scales because of climate change is difficult. Future work to study climate influence on denudation rates should focus on the successes of previous work that document transient denudation rates over shorter and more recent time scales, i.e., from the Last Glacial Maximum to present.
IntroductionDegenerative cervical myelopathy (DCM) is the most common cause of spinal cord impairment. Unfortunately, the condition remains poorly recognised and underdiagnosed. To better identify ...patients, screening tests that target individuals at high risk would be helpful. One group in particular known to have a high prevalence of DCM consists of patients with lumbar degenerative disease (LDD), with the combined presentation referred to as tandem stenosis. Given that LDD is one of the most common presentations in neurosurgical practice and primary care, it is the objective of the proposed study to administer a screening test to these patients as well as those with risk factors or symptoms which raise the suspicion of underlying DCM.Methods and analysisA screening test based on clinical signs/symptoms and known risk factors of DCM was designed. Screening will be performed in neurosurgical consultations for patients with LDD or those with any suspicion of myelopathy. Points are attributed based on the presence of signs/symptoms of DCM (eg, Hoffmann sign, hyper-reflexia) and for comorbidities that predispose or are frequently associated with cervical myelopathy (eg, rheumatoid arthritis, carpal tunnel syndrome). Patients with ≥3 points undergo cervical MRI examination. Patients with positive MRIs will be consulted and receive assessment via modified Japanese Orthopedic Association and Neck Disability Index scores, and subsequent clinical management will be based on practice guidelines. An exploratory multivariate analysis of the effectiveness and efficiency of this proposed screening test will be evaluated after positively screening 50 patients for DCM.Ethics and disseminationThis study has received research ethics approval from the Swiss Association of Research Ethics Committees (ID: 2020-02785). The results of this study will be disseminated in a journal targeting physicians commonly encountering patients with LDD.
Although the numbers of women in training and in entry-level academic positions in medicine have increased substantially in recent years, the proportion of women in senior faculty positions has not ...changed. We conducted a study to determine the contributions of background and training, academic productivity, distribution of work time, institutional support, career attitudes, and family responsibilities to sex differences in academic rank and salary among faculty members of academic pediatric departments.
We conducted a cross-sectional survey of all salaried physicians in 126 academic departments of pediatrics in the United States in January 1992. Of the 6441 questionnaires distributed, 4285 (67 percent) were returned. The sample was representative of U.S. pediatric faculty members. Multivariate models were used to relate academic rank and salary to 16 independent variables.
Significantly fewer women than men achieved the rank of associate professor or higher. For both men and women, higher salaries and ranks were related to greater academic productivity (more publications and grants), more hours worked, more institutional support of research, greater overall career satisfaction, and fewer career problems. Less time spent in teaching and patient care was related to greater academic productivity for both sexes. Women in the low ranks were less academically productive and spent significantly more time in teaching and patient care than men in those ranks. Adjustment for all independent variables eliminated sex differences in academic rank but not in salary.
Lower rates of academic productivity, more time spent in teaching and patient care and less time spent in research, less institutional support for research, and lower rates of specialization in highly paid subspecialties contributed to the lower ranks and salaries of female faculty members.
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