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The structural properties of polyfluorenes (PF) are extremely sensitive to the choice of functionalizing side chains. Dioctyl substituted PF (PF8) adopts metastable structures that depend upon the thermal history and choice of solvents used in film forming conditions. We present a detailed study of the changes in the backbone and side chain morphology in PF8, induced by the various crystallographic phases, using Raman scattering techniques. The vibrational frequencies and intensities of fluorene oligomers are calculated using hybrid density-functional theory with a 3-21G* basis set. The alkyl side chains are modeled as limiting conformations: all anti, anti-gauche-gauche, and end gauche representations. The calculated vibrational spectra of single chain oligomers in conjunction with our experimental results demonstrate the β phase, which is known to originate in regions of enhanced chain planarity as a direct consequence of the alkyl side chain conformation. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment especially for Non-Hodgkin-Lymphoma (NHL). This study evaluates the role of fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) in NHL treated with CAR T-cell therapy concerning response assessment and prognosis.We evaluated 34 patients with NHL who received a CAR T-cell therapy between August 2019 and July 2022. All patients underwent a pre-therapeutic FDG-PET/CT (PET-0) 6 days prior and a post-therapeutic FDG-PET/CT (PET-1) 34 days after CAR T-cell therapy. Deauville score (DS) was used for evaluation of response to therapy and compared to a minimum follow-up of 5 months.19/34 (55.9%) patients achieved DS ≤ 3 on PET-1, the remaining 15 (44.1%) patients had DS > 3 on PET-1. 14/19 patients with DS ≤ 3 on PET-1 had no relapsed or refractory (r/r)-disease and were still alive at last follow-up. The other 5 patients had r/r-disease and 4 of these died. Except for two patients who had no r/r-disease, all other patients (13/15) with DS > 3 on PET-1 had r/r-disease and 12 of these subsequently died. Patients with DS ≤ 3 on PET-1 had significantly better progression free survival (PFS; HR: 5.7; p < 0.01) and overall survival (OS; HR: 5.0; p < 0.01) compared to patients with DS > 3 on PET-1. In addition, we demonstrated that patients with DS ≤ 4 on PET-0 tended to have longer PFS (HR: 3.6; p = 0.05).Early FDG-PET/CT using the established DS after CAR T-cell therapy is a powerful tool to evaluate response to therapy., Competing Interests: RM received speaker fees from Kite/Gilead, Incyte, Servier. KM received speaker honoraria from Novartis outside of the submitted work. RW received consultant fees and honoraria from Amgen, BMS/Celgene, Janssen, Kite/Gilead, Novartis, Pfizer, Sanofi. RZ received speaker fees from Novartis, Incyte, MNK; Sanofi. No other potential conflicts of interest relevant to this article exist., (Thieme. All rights reserved.)

Background: Torsion of the spiral colon (TSC) describes twisting of the spiral colon around its mesentery. The present study reviewed the medical records of 58 cows and heifers with TSC and described the findings, treatment and outcome., Results: All cases had an abnormal general condition, and the main vital sign abnormalities were tachycardia (72.4%), tachypnoea (67.2%) and decreased rectal temperature (51.8%). Signs of colic were seen in 62.1% of the cows. The most common intestinal abnormalities were an empty or almost empty rectum (96.6%), reduced or absent rumen motility (93.2%), positive ballottement and/or percussion and simultaneous auscultation on the right side of the abdomen (87.9%), reduced or absent intestinal motility (84.5%) and dilatation of the large intestines (spiral colon and/or caecum, 70.7%) diagnosed by transrectal palpation. The main biochemical changes were hypermagnesaemia (70.8%), hypocalcaemia (70.8%), and acidosis (66.7%). Haemoconcentration was found in 63.8%. The main ultrasonographic findings were reduced to absent small intestinal motility (83.3%), dilated small intestines (69.6%) and ascites (66.7%). The spiral colon was dilated in 44.0% of the cows and the caecum in 24.0%. The actual site of torsion could not be visualised. Based on the clinical findings, TSC was diagnosed in 22.4% and caecal dilatation in 50.0% of the cows. A tentative diagnosis of small intestinal ileus was made in another 10.3% of the cows, and a definitive diagnosis of small intestinal ileus in 17.3%. Fifty-three cows underwent right flank laparotomy, and the TSC could be reduced in 26. Twenty-six of the 58 (44.8%) cows were discharged and 32 (55.2%) were euthanased before, during or after surgery., Conclusions: Acute illness, a sparse amount of faeces in the rectum and dilated spiral colon and caecum are characteristic findings of TSC. The final diagnosis often relies on the surgical or postmortem findings. Cattle with TSC should be treated surgically without delay. The prognosis is guarded with a survival rate of 44.8%., (© 2024. The Author(s).)

Objective: To describe the findings, treatment, and outcome of small intestinal volvulus (SIV) in 47 cows., Animals and Procedure: Retrospective analysis of medical records. Comparison of the findings for 18 surviving and 29 non-surviving cows., Results: The most common abnormal vital signs were tachycardia (68.0%), tachypnea (59.6%), and decreased rectal temperature (51.1%). Signs of colic occurred in 66.0% of cows in the study. Rumen motility was reduced or absent in 93.6% of cows, and intestinal motility in 76.6%. Clinical signs on ballottement and/or percussion and simultaneous auscultation were positive on the right side in 78.7% of cows. Transrectal examination showed dilated small intestines in 48.9% of cows. The rectum contained little or no feces in 93.6% of cows. The principal laboratory abnormalities were hypocalcemia (74.1%), hypokalemia (73.8%), azotemia (62.8%), hypermagnesemia (61.6%), and hemoconcentration (60.0%). The principal ultrasonographic findings were dilated small intestines (87.1%) and reduced or absent small intestinal motility (85.2%). Forty-one of the 47 cows underwent right flank laparotomy and the SIV was reduced in 21 cows. When comparing the clinical and laboratory findings of 18 surviving and 29 non-surviving cows, the groups differed significantly with respect to severely abnormal general condition (16.7 versus 37.9%), rumen stasis (22.2 versus 79.3%), intestinal atony (16.7 versus 48.3%), serum urea concentration (6.5 versus 9.8 mmol/L), and serum magnesium concentration (0.98 versus 1.30 mmol/L). In summary, 38.3% of the cows were discharged and 61.7% were euthanized before, during, or after surgery., Conclusion and Clinical Relevance: An acute course of disease, little or no feces in the rectum, and dilated small intestines were characteristic of SIV in this study population., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown 1-3 . Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy., (© 2024. The Author(s).)

Individual cognitive-behavioral therapy (CBT) is the recommended first-line psychological treatment for young people with obsessive-compulsive disorder (OCD), with good outcomes. However, because some young people only partially respond to CBT, it is necessary to improve treatment outcomes. This is the first study to explore the acceptability and satisfaction of a new multifamily therapy (MFT). Three groups were attended by 16 young people with OCD, their parents, and siblings. Parents and young people completed questionnaires and focus groups. Thematic analysis was applied to transcripts of focus groups. The majority of young people and parents (93.9%) were satisfied or very satisfied. Thematic analysis identified benefits, including increased understanding of OCD, support from the group, and a feeling of not being alone. Further research is required to establish the group's effectiveness on OCD symptom severity and to identify the factors that MFT addresses. MFT shows promise as an acceptable and satisfactory treatment.

Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring., (© 2023. Springer Nature Limited.)

Objective: To describe the clinical, laboratory, and ultrasonographic findings; treatment; and outcome of cattle with mesenteric torsion (MT)., Animals: 61 cattle with MT between November 1, 1986, and December 31, 2019., Methods: Medical records were retrospectively reviewed. Results were compared for cattle that survived versus did not survive to hospital discharge., Results: All cattle had abnormal demeanor. The most common clinical signs were tachycardia (80.3% [49/61]), tachypnea (65.0% [39/60]), and lower rectal temperature (59.3% [35/59]). Signs of colic occurred in 65.6% (40/61). The most common gastrointestinal findings were an empty or almost empty rectum (100% [59/59]), reduced or absent motility of the small intestines (96.6% [57/59]) or rumen (93.2% [55/59]), positive ballottement and/or percussion and simultaneous auscultation on the right side (91.7% [55/60]), and dilated small (49.2% [29/59]) and large intestines (spiral colon and/or cecum, 44.1% [26/59]) detected during transrectal examination. The most common laboratory findings were acidosis (82.6%, [38/46]) hypermagnesemia (74.5% [35/47]). Ultrasonographic findings included reduced or absent small intestinal motility (86.7% [26/30]) and dilated small intestines (83.8% [31/37]). The spiral colon was dilated in 32.4% (12/37) of the cattle. Eighty-two percent (50/61) of the cattle underwent right flank laparotomy and the MT could be reduced in 34.4% (21/61). Twenty-three percent (14/61) of the cattle survived to hospital discharge, and 77.0% (47/61) were euthanized before hospital discharge., Clinical Relevance: Dilated small and large intestines (spiral colon, cecum) combined with a severely abnormal demeanor and tachycardia are characteristic findings in cows with MT. Immediate surgical treatment is paramount.

Objective: Age-related macular degeneration (AMD) is the leading cause of vision loss in older populations of industrialized countries. Antibody-based therapy inhibiting the vascular endothelial growth factor (VEGF) has been very successful in the treatment of the neovascular form of AMD. This retrospective clinical study investigates the baseline characteristics and progression of neovascular age-related macular degeneration (nAMD) in patients who received over 60 anti-VEGF intravitreal injections. Methods: Retrospective analysis of 6812 eyes of 5678 patients undergoing anti-VEGF treatment at our clinic between November 2006 and December 2017 yielded 12 eyes of 12 patients who had received more than 60 intravitreal injections into one eye. We re-evaluated the baseline characteristics of visual acuity, intraocular pressure, optical coherence tomography, fluorescein angiography, as well as autofluorescence and analyzed the documented disease progress as monitored in our daily clinical practice. Data on the fellow eye were also analyzed. Results: Each of our 12 patients had the injected anti-VEGF agent (bevacizumab, ranibizumab, or aflibercept) changed at least once during treatment. After initial improvement, visual acuity decreased in most patients over time. The 2 patients with the best visual acuity at the beginning also showed the best visual acuity at the end of the study. No significant change was observed in the intraocular pressure. Conclusions: After the initial improvement, visual acuity decreased over time. Good visual acuity at the beginning of the study increased the chances of maintaining the same level throughout the treatment. Intravitreal treatment did not affect intraocular pressure. Abbreviations: AMD = age-related macular degeneration, nAMD = neovascular age-related macular degeneration, VEGF = vascular endothelial growth factor, OCT = optical coherence tomography, VA = visual acuity, PDT = photodynamic therapy., (#x00A9; The Authors.Romanian Society of Ophthalmology.)

Ribosomally synthesized and post-translationally modified peptide natural products have provided many highly unusual scaffolds. This includes the intriguing alkaloids crocagins, which possess a tetracyclic core structure and whose biosynthesis has remained enigmatic. Here we use in vitro experiments to demonstrate that three proteins, CgnB, CgnC and CgnE, are sufficient for the production of the hallmark tetracyclic crocagin core from the precursor peptide CgnA. The crystal structures of the homologues CgnB and CgnE reveal them to be the founding members of a peptide-binding protein family and allow us to rationalize their distinct functions. We further show that the hydrolase CgnD liberates the crocagin core scaffold, which is subsequently N-methylated by CgnL. These insights allow us to propose a biosynthetic scheme for crocagins. Bioinformatic analyses based on these data led to the discovery of related biosynthetic pathways that may provide access to a structurally diverse family of peptide-derived pyrroloindoline alkaloids., (© 2023. The Author(s).)

Background: Intussusception is a form of ileus of the intestines in which an oral intestinal segment slides into the adjacent aboral intestinal segment, causing obstruction of the bowel., Methods: We analysed the medical records of 126 cattle with intussusception of the small intestine., Results: Demeanour and appetite were abnormal in 123 cattle. Non-specific signs of pain occurred in 26.2%, signs of visceral pain in 46.8% and signs of parietal pain in 56.4%. Intestinal motility was decreased or absent in 93.7% of the cattle. The most common findings of transrectal palpation were rumen dilation (37.3%) and dilated small intestines (24.6%). In 96% of the cattle, the rectum was empty or contained little faeces. The principal laboratory findings were hypokalaemia (89.6%), hypocalcaemia (76.5%), base excess (72.9%), hypochloraemia (71.8%), azotaemia (62.1%) and haemoconcentration (61.1%). The main ultrasonographic findings were reduced or absent intestinal motility (98.2%) and dilated small intestines (96.0%). A diagnosis of ileus was made in 87.8% and a diagnosis of ileus attributable to intussusception was made in another 9.8%. Right-flank laparotomy was carried out in 114 cattle. Fifty-six (44.4%) cows were discharged., Conclusions: Clinical findings of intussusception in cattle are often non-specific. Ultrasonography may be required to diagnose ileus., Competing Interests: The authors declare they have no conflicts of interest., (© 2023 The Authors. Veterinary Record Open published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Myxobacteria have proven to be a rich source of natural products, but their biosynthetic potential seems to be underexplored given the high number of biosynthetic gene clusters present in their genomes. In this study, a truncated ajudazol biosynthetic gene cluster in Cystobacter sp. SBCb004 was identified using mutagenesis and metabolomics analyses and a set of novel ajudazols (named ajudazols C-J, 3 - 10 , respectively) were detected and subsequently isolated. Their structures were elucidated using comprehensive HR-MS and NMR spectroscopy. Unlike the known ajudazols A ( 1 ) and B ( 2 ), which utilize acetyl-CoA as the biosynthetic starter unit, these novel ajudazols were proposed to incorporate 3,3-dimethylacrylyl CoA as the starter. Ajudazols C-J ( 3 - 10 , respectively) are characterized by varying degrees of hydroxylation, desaturation, and different glycosylation patterns. Two P450-dependent enzymes and one glycosyltransferase are shown to be responsible for the hydroxylation at C-8, the desaturation at C-15 and C-33, and the transfer of a d- β -glucopyranose, respectively, based on mutagenesis results. One of the cytochrome P450-dependent enzymes and the glycosyltransferase were found to be encoded by genes located outside the biosynthetic gene cluster. Ajudazols C-H ( 3 - 8 , respectively) exhibit cytotoxicity against various cancer cell lines.

When searching for new antibiotics against Gram-negative bacterial infections, a better understanding of the permeability across the cell envelope and tools to discriminate high from low bacterial bioavailability compounds are urgently needed. Inspired by the phospholipid vesicle-based permeation assay (PVPA), which is designed to predict non-facilitated permeation across phospholipid membranes, outer membrane vesicles (OMVs) of Escherichia coli either enriched or deficient of porins are employed to coat filter supports for predicting drug uptake across the complex cell envelope. OMVs and the obtained in vitro model are structurally and functionally characterized using cryo-TEM, SEM, CLSM, SAXS, and light scattering techniques. In vitro permeability, obtained from the membrane model for a set of nine antibiotics, correlates with reported in bacterio accumulation data and allows to discriminate high from low accumulating antibiotics. In contrast, the correlation of the same data set generated by liposome-based comparator membranes is poor. This better correlation of the OMV-derived membranes points to the importance of hydrophilic membrane components, such as lipopolysaccharides and porins, since those features are lacking in liposomal comparator membranes. This approach can offer in the future a high throughput screening tool with high predictive capacity or can help to identify compound- and bacteria-specific passive uptake pathways., (© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)