julilili42/papers huggingface dataset:
BRAF Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability
2023-09-01

In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF Δβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF Δβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF ΔLNVTAP&gt;F and two novel mutants, BRAF delinsFS and BRAF ΔLNVT&gt;F , and compare them with other BRAF Δβ3-αC oncoproteins. We show that BRAF Δβ3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAF Δβ3-αC oncoproteins, e.g., BRAF ΔLNVTAP&gt;F , increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAF Δβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.
Quantum resonant optical bistability with a narrow atomic transition: bistability phase diagram in the bad cavity regime
2023-09-01

Abstract We report on the observation of a novel manifestation of saturation-induced optical bistability in a resonantly pumped optical ring cavity interacting strongly with a cloud of atoms via a narrow atomic transition. The bistability emerges, above a critical pump rate, as an additional peak in the cavity’s normal mode spectrum close to atomic resonance. This third transmission peak is usually suppressed due to strong resonant absorption, but in our experiment it is visible because of the linewidth of the atomic transition being much smaller than that of the cavity, which sets the experiment into the bad-cavity regime. Relying on complete saturation of the transition, this bistability has a quantum origin and cannot be mimicked by a classical material presenting a nonlinear refraction index. The appearance of the central peak in addition to the normal modes is predicted by a semi-classical model derived from the Tavis–Cummings Hamiltonian from which we derive a bistability phase diagram that connects our observations with former work on optical bistability in the good cavity regime. The phase diagram reveals several so far unexplored bistable phases.
Optimising verbal fluency analysis in neurological patients with dysarthria: examples from Parkinson’s disease and hereditary ataxia
2023-09-01

Dysarthria severity can be estimated based on speech samples derived from VFT. Dysarthria can lead to lower total correct items and is associated with more ambiguous verbalizations in VFT. Dysarthria severity should be considered when interpreting VFT performance in common movement disorders.
The stratigraphy and formation of Middle Stone Age deposits in Cave 1B, Klasies River Main site, South Africa, with implications for the context, age, and cultural association of the KRM 41815/SAM-AP 6222 human mandible
2023-09-01

Cave 1B, in the Klasies River Main site complex (KRM), is best known for the recovery of the KRM 41815/SAM-AP 6222 human mandible. After initial skepticism over the modernity of this specimen, it is accepted that the mix of archaic and modern traits it displays is characteristic of early Homo sapiens individuals. Different authors have associated this specimen with the Middle Stone Age (MSA) I and II/Mossel Bay cultural phases, but the published data do not allow an unambiguous attribution. KRM 41815's frequent use in studies of the evolution of the human mandible, and its well-developed chin, makes clarifying its age and context important objectives. The field and micromorphology observations presented here provide greater insight into the stratigraphy and formation of the sequence exposed in the PP38 excavation. There are three major divisions: the basal Light Brown Sand (LBS) Member (not excavated), the Rubble Sand (RS) Member (MSA I), and the Shell and Sand Dark Carbonized (SASDC) Submember (MSA II). Cultural stratigraphy based on lithic artifacts remains the only way to make secure (but broad) temporal correlations with the rest of the site complex. This investigation shows that a range of anthropogenic, geogenic, and biogenic processes contributed to the deposition and post-depositional alteration of the identified microfacies. Short depositional hiatuses are reasonably common, and a significant hiatus was identified between the RS and SASDC. The impact of post-depositional processes on the RS is significant, with anthropogenic deposits poorly preserved. In comparison, the SASDC is dominated by hearths contained within deposits rich in reworked anthropogenic materials known as carbonized partings. Small shell disposal features are also present. The distribution of these anthropogenic features suggests continuity in the management of space throughout the MSA II occupations, from before 110 ka. New stratigraphic correlations indicate that KRM 41815 is unambiguously associated with the MSA I. Therefore, it predates 110 ka, with a lower age limit potentially in Marine Isotope Stage 6.
Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses
2023-09-01

Abstract Purpose In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO). Methods We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T 1 -enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined. Results Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T 1 -enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm. Conclusion The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.
New Intravesical Agents for BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer
2023-09-01

BACKGROUND: With the exception of the FDA-approved valrubicin and pembrolizumab, there are no standard second-line treaments for BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC). OBJECTIVES: To provide a systematic review of the novel intravesically administered therapeutic agents for the salvage treatment of BCG-unresponsive NMIBC. METHODS: Online search of the PubMed, EMBASE and Web of Science databases was performed. The endpoints of this review were to evaluate the efficacy of the agents in terms of complete response rates (CR) and durability of CR, overall survival, recurrence-free survival and cancer-specific survival and to report on their toxicity profile. A search on Clinicaltrials.gov was performed to identify ongoing clinical trials. RESULTS: 14 studies were included in this review. The critical clinical need for the development of an effective, safe and durable intravesical drug for the salvage treatment of high-risk NMIBC seems to be met mainly by intravesical gene therapy; in fact, data support the FDA-approved nadofaragene firadenovec as a potentially important therapeutic advancement in this context. Promising results are also being obtained by the combination of N-803/BCG and by innovative drug delivery systems. CONCLUSIONS: Considering the plethora of novel intravesical treatments that have completed phase II evaluation, one can reasonably expect that clinicians will soon have at their disposal new agents and treatment options for BCG-unresponsive NMIBC. In the near future, it will be up to the urologist to identify, for each specific patient, the right agent to use, based on safety, results and cost-effectiveness.
Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3
2023-09-01

ABSTRACT Increased neurofilament light (NfL; NEFL) protein in biofluids is reflective of neurodegeneration and has gained interest as a biomarker across neurodegenerative diseases. In spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, patients exhibit progressive NfL increases in peripheral blood when becoming symptomatic, and NfL remains stably elevated throughout further disease course. However, progressive NfL changes are not yet validated in relevant preclinical SCA3 animal models, hindering its application as a biomarker during therapeutic development. We used ultra-sensitive single-molecule array (Simoa) to measure blood NfL over disease progression in YACQ84 mice, a model of SCA3, assessing relationships with measures of disease severity including age, CAG repeat size and magnetic resonance spectroscopy. YACQ84 mice exhibited plasma NfL increases that were concomitant with ataxia-related motor deficits as well as increased serum NfL, which correlated with previously established neurometabolite abnormalities, two relevant measures of disease in patients with SCA3. Our findings establish the progression of NfL increases in the preclinical YACQ84 mouse, further supporting the utility of blood NfL as a peripheral neurodegeneration biomarker and informing on coinciding timelines of different measures of SCA3 pathogenesis.
Inflammatory Myofibroblastic Tumor With ROS1 Gene Fusions in Children and Young Adolescents
2023-09-01

PURPOSE Inflammatory myofibroblastic tumors (IMTs) are often driven by anaplastic lymphoma kinase fusions and less frequently by alternative fusions such as ROS1. We describe the clinical characteristics, treatment approach, and outcome for a series of young patients with IMTs and ROS1 alterations. METHODS This was a retrospective, international, multicenter study analyzing young patients (younger than 21 years) with ROS1-altered IMTs treated in 10 European referral centers between 2014 and 2022. Patients were included in the European pediatric Soft tissue sarcoma Study Group NRSTS-2005 protocol or registered in the Soft Tissue Sarcoma Registry. Primary surgery was recommended if a microscopic radical resection was feasible without mutilation. No standard systemic treatment protocol was available, but several medical options were recommended. RESULTS A total of 19 patients (median age 8.3 years) were included. Most patients had a biopsy at diagnosis (Intergroup Rhabdomyosarcoma Study [IRS] I; n = 2, IRS II; n = 1, IRS III biopsy; n = 11, IRS III resection; n = 3, IRS IV; n = 2). Twelve patients received neoadjuvant systemic therapy in first line (four received multiple treatments): high-dose steroids (n = 2), vinorelbine/vinblastine with methotrexate (n = 6), or ROS1 inhibitors (n = 8). After a median follow-up of 2.8 years (range, 0.2-13.4), seven patients developed an event. The 3-year event-free survival was 41% (95% CI, 11 to 71), and the 3-year overall survival was 100%. CONCLUSION Outcome for ROS1-altered IMTs appears excellent. A complete resection at diagnosis was often not feasible, and most patients needed neoadjuvant therapy. Patients who developed a tumor event could be cured with reinitiation of systemic therapy and/or surgery. This approach illustrates a switch in treatment philosophy moving from immediate, often mutilating, surgery to systemic (targeted) therapy as a bridge to more conservative surgery later in the treatment course.
#556 Reproductive outcomes after fertility-sparing surgery for cervical cancer – results of the fertiss study
2023-09-01

<h3>Introduction/Background</h3> The goal of fertility-sparing treatment (FST) for patients with cervical cancer is to achieve comparable oncologic outcomes to those after radical treatment while maximizing reproductive outcomes, which include the ability to conceive and minimizing the risk of preterm birth. <h3>Methodology</h3> Patients from the international multicentre retrospective FERTISS study, which included women treated with any type of FST, were analysed for information on timing of FST in relation to pregnancy, attempts to conceive, mode of conception, prophylactic procedures to reduce the risk of severe prematurity, rate of pregnancy failure, overall duration of pregnancy and mode of termination. <h3>Results</h3> Of the 733 patients treated at 44 centres in 13 countries, only half (49.7%) attempted to become pregnant during follow-up (median 72 months). Unsuccessful attempts were recorded in 27.0% (198/733) of patients, while 22.6% (166/733) were successful. Of these patients, 63.2% (122/193) underwent non-radical surgery and 25.7% (44/171) underwent radical trachelectomy (p &lt; 0.001). Data from 124 patients (74.7%) were available for detailed analysis. A total of 91.7% (111/124) patients became pregnant naturally. The abortion rate in the first pregnancy did not differ between patients after radical and non-radical procedures. There was no difference in delivery success rates between patients after non-radical and radical FST (86% vs. 83%, p=0.77). Preterm delivery (&lt;38 weeks gestation) occurred more frequently in patients after radical than non-radical procedures (76.5% vs. 57.7%, p=0.15). Almost all patients (97.3%) with ultrasound cervicometry delivered, in contrast to women without cervicometry (30.6%), (p&lt;0.001). <h3>Conclusion</h3> Half of the patients did not attempt pregnancy at all after FST. Patients who underwent non-radical surgery had higher pregnancy rates. Most women who became pregnant delivered a viable fetus, but women who underwent radical trachelectomy had a higher rate of preterm births in the severe prematurity range. Ultrasound cervicometry showed a significant effect on the prevention of preterm birth.
Phonetic characteristics of German unstressed vowels: The case of opa vs Oper
2023-09-01

Kohler [Einführung in die Phonetik des Deutschen (Erich Schmidt Verlag, Berlin, Germany, 1995)] stated that German [ɐ] and [a] in unstressed syllables are merging. The present study tested this hypothesis. The contrast was found intact word-internally and word-finally. Neighborhood density enhanced its phonetic characteristics, but no effects of frequency and conditional probability were found.
P22.03.A FEASIBILITY OF AND COMPLIANCE TO ELECTRONIC PATIENT-REPORTED OUTCOME ASSESSMENT IN THE MOLECULAR TUMOR BOARD IN (NEURO-)ONCOLOGICAL PATIENTS UNDER TARGETED THERAPY (TRACE)
2023-09-01

Abstract BACKGROUND Comprehensive genomic profiling and biomarker-based therapies are increasingly used in clinical trials and in innovative health care systems including the center for personalized medicine network. Systematic assessments of patient-reported outcomes (PRO) are warranted to gain insight into the perspective of patients during biomarker-based therapies. In the present study, we focused on the feasibility of and compliance to an electronic PRO assessment in patients treated at our center. MATERIAL AND METHODS Based on a retrospective evaluation of symptom burden in 265 neurooncology patients in the Molecular Tumor Board (MTB), we developed an app by 14 expert rounds including validated assessments of health-related quality of life (HRQoL), burden of symptoms und psychological stress, and tested it in a pilot study. After informed consent, patients were introduced to the app by study staff and completed subsequently patient-reported outcomes at several time points (weekly, monthly, and quarterly). We conducted a structured interview with health care personnel and the patients as users after 3 months to assess the app’s usability and feasibility. The interview was transcribed and analyzed according to Mayring ́s qualitative content analysis regarding handling, feasibility and applicability in daily routine.Furthermore, we assessed compliance and descriptive data of the ePROs. RESULTS So far, 14 patients and caregivers have been enrolled, (9 female, 5 male). Median age was 50 years (range 28 -79), 3 out of 14 patients dropped out due to death. A total of 4 study staff members, 9 patients and one caregiver were interviewed regarding usability /feasibility. Both evaluated as good (study staff members in total n=40 quotes, patients/caregivers n=112 quotes). Main advantages were the possibility to complete questionnaires at home and the easy implementation in daily life. Compliance to questionnaires was high, e.g., 91% of weekly distributed NCCN Distress Thermometer were answered in time (range 65-100%, assessment duration 5-56 weeks, 262 answers), we observed a median Distress score of 4 (range 0-9, n=262, weekly assessed) and a median Global health score of 66.7 (range 16.7-100, n=69, EORTC QLQ-C30, question 29 and 30, monthly assessed, compliance 94%). CONCLUSION This pilot study proved feasibility and acceptance of the app and might enable PRO assessment during biomarker-guided therapies.
KS01.5.A LATE BREAKING ABSTRACT: LONG-TERM FOLLOW-UP OF PATIENTS WITH NEWLY DIAGNOSED IDH-MUTANT ASTROCYTOMA AFTER IDH1-VAC TREATMENT
2023-09-01

Abstract BACKGROUND The Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), a multicenter, single-arm, open-label, first-in-human phase I trial, met its primary endpoints in demonstrating safety and immunogenicity of a long peptide vaccine targeting IDH1(R132H) (IDH1-vac) added to standard of care in 32 patients with newly diagnosed World Health Organization (WHO) Grade 3 (n=21) and 4 (n=11) IDH1(R132H)+ astrocytomas (ClinicalTrials.gov identifier NCT02454634). MATERIAL AND METHODS Here, we report on the clinical and immunological long-term follow-up of NOA16. Data cut-off was May 2023. RESULTS Six-year progression-free and survival rates of patients in the safety data set were 0.47 (CI: 0.29 - 0.63) and 0.66 (CI: 0.46 - 0.79), respectively. Six-year progression-free and survival rates in the Grade 3 population were 0.52 (CI: 0.30 - 0.71) and 0.67 (CI: 0.43 - 0.83), respectively. Six-year progression-free and survival rates in the Grade 4 population were 0.55 (CI: 0.23 - 0.78) and 0.62 (CI: 0.28 - 0.84), respectively. Six-year progression-free and survival rates in patients with complete resection (n=17) were 0.82 (CI: 0.55 - 0.94) and 0.88 (CI: 0.61 - 0.97), respectively. Calculated via the Simon-Makuch method, patients in the immunogenicity dataset (n=30) with immune responses (IR) had six-year progression-free and survival rates of 0.46 (0.26 - 0.64) and 0.75 (CI: 0.55 - 0.87), respectively. Two patients without IR showed progressive disease (PD) within two years of first diagnosis and died within 3 years of first diagnosis. In one-year landmark analyses, best mutation-specific B cell response at the time point of last vaccination or later was associated with a favorable clinical course, suggesting a relevant but differential response to repetitive therapeutic vaccination regimes. CONCLUSION This data supports a randomized clinical trial of IDH-vac in patients with newly diagnosed IDH-mutant gliomas. A booster treatment regime should be considered as continuous source of IDH1R132H-reactive T cells.
Can Genome Sequencing Coupled to Flux Balance Analyses Offer Precision Guidance for Industrial Strain Development? The Lessons from Carbon Trafficking in Corynebacterium glutamicum ATCC 21573
2023-09-01

Systems biology tools offer new prospects for industrial strain selection. For bacteria that are significant for industrial applications, whole-genome sequencing coupled to flux balance analysis (FBA) can help unpack the complex relationships between genome mutations and carbon trafficking. This work investigates the l -tyrosine ( l -Tyr) overproducing model system Corynebacterium glutamicum ATCC 21573 with an eye to more rational and precision strain development. Using genome-wide mutational analysis of C. glutamicum , we identified 27,611 single nucleotide polymorphisms and 479 insertion/deletion mutations. Mutations in the carbon uptake machinery have led to phosphotransferase system-independent routes as corroborated with FBA. Mutations within the central carbon metabolism of C. glutamicum impaired the carbon flux, as evidenced by the lower growth rate. The entry to and flow through the tricarboxylic acid cycle was affected by mutations in pyruvate and α-ketoglutarate dehydrogenase complexes, citrate synthase, and isocitrate dehydrogenase. FBA indicated that the estimated flux through the shikimate pathway became larger as the l -Tyr production rate increased. In addition, protocatechuate export was probabilistically impossible, which could have contributed to the l -Tyr accumulation. Interestingly, aroG and cg0975 , which have received previous attention for aromatic amino acid overproduction, were not mutated. From the branch point molecule, prephenate, the change in the promoter region of pheA could be an influential contributor. In summary, we suggest that genome sequencing coupled with FBA is well poised to offer rational guidance for industrial strain development, as evidenced by these findings on carbon trafficking in C. glutamicum ATCC 21573.
Scalable mesh microelectrode arrays for neural spheroids and organoids
2023-09-01

Abstract Introduction: Neural organoids promise to help understand the human brain and develop treatments for neurological diseases. Electrophysiological recordings are essential in neural models to evaluate the activity of neural circuits. Mesh microelectrode arrays (MEAs) have been demonstrated to be suitable for organoids and spheroids, and there is demand for easy-to-use devices that can be manufactured at scale. Methods: We present a new mesh MEA device with an easyto- use design. We produce mesh MEA chips on 100 mm carrier wafers and connect individual chips to PCBs by wirebonding. The devices are completed by assembly of a twopiece well and a glass cover slip. Results: Each device contains a suspended hammock-like mesh with 64 microelectrodes. The square grid’s pitch of 200 μm makes the mesh suitable for typical organoid sizes while spreading the electrodes across a 1.4 mm region. The well is designed for fluid handling by pipetting or pump systems. Impedance measurements indicate a high yield of functional microelectrodes, although further effort is needed to produce consistent low impedances. The devices are compatible with commercial amplifiers, while adaptation of the PCB to other formats will be straightforward. Conclusions: Using scalable production methods, we have developed a mesh MEA device design that offers improved ease-of-use. Next steps will include biological validation in collaboration with partners.