Decisions about dendritic cells: past, present, and future.

A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.

T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10.

Functionally diverse T cell populations interact to maintain homeostasis of the immune system. We found that human and mouse antigen-activated T cells with high expression of the lymphocyte surface marker CD52 suppressed other T cells. CD52(hi)CD4(+) T cells were distinct from CD4(+)CD25(+)Foxp3(+) regulatory T cells. Their suppression was mediated by soluble CD52 released by phospholipase C. Soluble CD52 bound to the inhibitory receptor Siglec-10 and impaired phosphorylation of the T cell receptor-associated kinases Lck and Zap70 and T cell activation. Humans with type 1 diabetes had a lower frequency and diminished function of CD52(hi)CD4(+) T cells responsive to the autoantigen GAD65. In diabetes-prone mice of the nonobese diabetic (NOD) strain, transfer of lymphocyte populations depleted of CD52(hi) cells resulted in a substantially accelerated onset of diabetes. Our studies identify a ligand-receptor mechanism of T cell regulation that may protect humans and mice from autoimmune disease.

Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas.

Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells. Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide and live or dead gram-negative bacteria. Mobilization requires TLR4 and its CD14 coreceptor and Trif. When tested for antigen-presenting function, Mo-DCs are as active as classical DCs, including cross-presentation of proteins and live gram-negative bacteria on MHC I in vivo. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via L-selectin and CCR7. Thus the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC-SIGN(+) cells with critical functions of DCs.

Real-world performance of Uromonitor® in urothelial bladder cancer detection: a multicentric trial.

OBJECTIVES: To compare Uromonitor® (U-Monitor Lda, Porto, Portugal), a multitarget DNA assay that detects mutated proto-oncogenes (telomerase reverse transcriptase [TERT], fibroblast growth factor receptor 3 [FGFR-3], Kirsten rat sarcoma viral oncogene homologue [KRAS]), with urine cytology in the urine-based diagnosis of urothelial carcinoma of the bladder (UCB) within a multicentre real-world setting. PATIENTS AND METHODS: This multicentre, prospective, double-blind study was conducted across four German urological centres from 2019 to 2024. We evaluated the diagnostic performance of Uromonitor compared to urine cytology in a cohort of patients with UCB and in healthy controls within a real-world setting. Sensitivity, specificity, positive-predictive value (PPV), negative-predictive value (NPV), and accuracy of the tests were measured, in addition to multivariate analyses to assess the ability of individual proto-oncogene mutations in detecting UCB. The biometric sample size was designed to achieve a 10% difference in sensitivity. RESULTS: Patients with UCB comprised 63.7% (339/532) of the study group. Uromonitor showed a sensitivity, specificity, PPV, NPV, accuracy, and an area-under-the-curve of 49.3%, 93.3%, 92.8%, 51.1%, 65.2%, and 0.713%, respectively. These metrics did not demonstrate statistical superiority over urine cytology in terms of sensitivity (44.6%; P = 0.316). Moreover, the comparison of additional test parameters, as well as the comparison within various sensitivity analyses, yielded no significant disparity between the two urinary tests. Multivariate logistic regression underscored the significant predictive value of a positive Uromonitor for detecting UCB (odds ratio [OR] 9.03; P < 0.001). Furthermore, mutations in TERT and FGFR-3 were independently associated with high odds of UCB detection (OR 13.30 and 7.04, respectively), while KRAS mutations did not exhibit predictive capability. CONCLUSION: Despite its innovative approach, Uromonitor fell short of confirming the superior results anticipated from previous studies in this real-world setting. The search for an optimal urine-based biomarker for detecting and monitoring UCB remains ongoing. Results from this study highlight the complexity of developing non-invasive diagnostic tools and emphasise the importance of continued research efforts to refine these technologies.

Improving detection of carcinoma in situ in bladder cancer: urinary cytology vs the Xpert® BC Monitor.

OBJECTIVE: To investigate and compare the performance of urinary cytology and the Xpert BC Monitor test in the detection of bladder cancer in various clinically significant patient cohorts, including patients with carcinoma in situ (CIS), in a prospective multicentre setting, aiming to identify potential applications in clinical practice. PATIENTS AND METHODS: A total of 756 patients scheduled for transurethral resection of bladder tumour (TURBT) were prospectively screened between July 2018 and December 2020 at six German University Centres. Central urinary cytology and Xpert BC Monitor tests were performed prior to TURBT. The diagnostic performance of urinary cytology and the Xpert BC Monitor was evaluated according to sensitivity (SN), specificity (SC), negative predictive value (NPV) and positive predictive value (PPV). Statistical comparison of urinary cytology and the Xpert BC Monitor was conducted using the McNemar test. RESULTS: Of 756 screened patients, 733 (568 male [78%]; median [interquartile range] age 72 [62-79] years) were included. Bladder cancer was present in 482 patients (65.8%) with 258 (53.5%) high-grade tumours. Overall SN, SC, NPV and PPV were 39%, 93%, 44% and 92% for urinary cytology, and 75%, 69%, 59% and 82% for the Xpert BC Monitor. In patients with CIS (concomitant or solitary), SN, SC, NPV and PPV were 59%, 93%, 87% and 50% for urinary cytology, and 90%, 69%, 95% and 50% for the Xpert BC Monitor. The Xpert BC Monitor missed four tumours (NPV = 98%) in patients with solitary CIS, while potentially avoiding 63.3% of TURBTs in inconclusive or negative cystoscopy and a negative Xpert result. CONCLUSION: Positive urinary cytology may indicate bladder cancer and should be taken seriously. The Xpert BC Monitor may represent a useful diagnostic tool for correctly identifying patients with solitary CIS and unsuspicious or inconclusive cystoscopy.

Integration of child life into adult oncology: A mixed-methods feasibility study.

BACKGROUND: Cancer in a loved one can have negative effects on child health and development. Child Life Specialists (CLSs) specialize in assisting children understand and cope with difficult medical scenarios but are generally not available in adult care facilities to support the needs of patient-families with minor children. We conducted a mixed-methods study of the implementation of a pilot CLS program at a tertiary oncology centre. METHODS: We collected administrative and clinical data on referred families; encounter data; and patient-reported questionnaire data before and 2 months after engagement with the program. RESULTS: Over the initial 10 months, 98 families were referred, 91 of whom engaged through a total of 257 clinical encounters. The cancer patient in the family was most commonly a woman with a mean age of 45 years and in the role of mother. Breast cancer was the most common diagnosis (24%) and 78% of patients had stage IV disease. Most families had >1 child at home, and children were most commonly school-aged (5-14y). Phone and Hospital/Clinic visits accounted for the largest portion of CLS time. Interventions ranged from diagnosis education through to bereavement support. Most cancer patients indicated that the program was helpful to them and their families. There were trends of moderate improvements on patient reported outcomes. CONCLUSION: Our study was able to provide an understanding of the initial CLS program operations to guide program development and future study. Such a program holds promise as an important aspect of adult oncology family-centered care.

The Nitrous Oxide Project: assessment of advocacy and national directives to deliver mitigation of anaesthetic nitrous oxide.

The environmental emissions attributed to anaesthetic nitrous oxide across the NHS are comparable to the carbon dioxide released by 135,000 flights from Frankfurt to New York. Much of these emissions are attributable to cumbersome and inadequately managed piped systems, resulting in excessive loss and waste. Since 2020, multiple hospital sites have been engaging with the Nitrous Oxide Project, a quality improvement method supporting a 'lean systems' approach to the provision of nitrous oxide. This review considers the frameworks supporting medical gas management in UK healthcare systems, and the impact of professional advocacy and medical gas stewardship to drive anaesthetic nitrous oxide mitigation in the NHS. Nitrous oxide mitigation efforts by grassroots and professional advocacy networks are enhanced through national centralised emission monitoring, distribution of data, technical information and provision of quality analysis. Given the climate harms of nitrous oxide, concerted efforts should be made to rationalise its use, and resources should be committed to supporting this at local, regional and national levels.

Robust Coding of Eye Position in Posterior Parietal Cortex despite Context-Dependent Tuning.

Neurons in posterior parietal cortex (PPC) encode many aspects of the sensory world (e.g., scene structure), the posture of the body, and plans for action. For a downstream computation, however, only some of these dimensions are relevant; the rest are "nuisance variables" because their influence on neural activity changes with sensory and behavioral context, potentially corrupting the read-out of relevant information. Here we show that a key postural variable for vision (eye position) is represented robustly in male macaque PPC across a range of contexts, although the tuning of single neurons depended strongly on context. Contexts were defined by different stages of a visually guided reaching task, including (1) a visually sparse epoch, (2) a visually rich epoch, (3) a "go" epoch in which the reach was cued, and (4) during the reach itself. Eye position was constant within trials but varied across trials in a 3 × 3 grid spanning 24° × 24°. Using demixed principal component analysis of neural spike-counts, we found that the subspace of the population response encoding eye position is orthogonal to that encoding task context. Accordingly, a context-naive (fixed-parameter) decoder was nevertheless able to estimate eye position reliably across contexts. Errors were small given the sample size (∼1.78°) and would likely be even smaller with larger populations. Moreover, they were comparable to that of decoders that were optimized for each context. Our results suggest that population codes in PPC shield encoded signals from crosstalk to support robust sensorimotor transformations across contexts.SIGNIFICANCE STATEMENT Neurons in posterior parietal cortex (PPC) which are sensitive to gaze direction are thought to play a key role in spatial perception and behavior (e.g., reaching, navigation), and provide a potential substrate for brain-controlled prosthetics. Many, however, change their tuning under different sensory and behavioral contexts, raising the prospect that they provide unreliable representations of egocentric space. Here, we analyze the structure of encoding dimensions for gaze direction and context in PPC during different stages of a visually guided reaching task. We use demixed dimensionality reduction and decoding techniques to show that the coding of gaze direction in PPC is mostly invariant to context. This suggests that PPC can provide reliable spatial information across sensory and behavioral contexts.

The spatiotemporal spread of human migrations during the European Holocene.

The European continent was subject to two major migrations of peoples during the Holocene: the northwestward movement of Anatolian farmer populations during the Neolithic and the westward movement of Yamnaya steppe peoples during the Bronze Age. These movements changed the genetic composition of the continent's inhabitants. The Holocene was also characterized by major changes in vegetation composition, which altered the environment occupied by the original hunter-gatherer populations. We aim to test to what extent vegetation change through time is associated with changes in population composition as a consequence of these migrations, or with changes in climate. Using ancient DNA in combination with geostatistical techniques, we produce detailed maps of ancient population movements, which allow us to visualize how these migrations unfolded through time and space. We find that the spread of Neolithic farmer ancestry had a two-pronged wavefront, in agreement with similar findings on the cultural spread of farming from radiocarbon-dated archaeological sites. This movement, however, did not have a strong association with changes in the vegetational landscape. In contrast, the Yamnaya migration speed was at least twice as fast and coincided with a reduction in the amount of broad-leaf forest and an increase in the amount of pasture and natural grasslands in the continent. We demonstrate the utility of integrating ancient genomes with archaeometric datasets in a spatiotemporal statistical framework, which we foresee will enable future studies of ancient populations' movements, and their putative effects on local fauna and flora.

Volumetric changes in the upper airway on CBCT after dentofacial orthopedic interventions - a systematic review.

OBJECTIVE: To provide a critical overview of the effect of various orthodontic and/or dentofacial orthopedic interventions on three-dimensional volumetric changes in the upper airway. MATERIALS AND METHODS: Four databases were searched for clinical studies concerning 3D volumetric assessments based on CBCT before and after orthodontics interventions. The quality of the studies was assessed using the quality assessment tool of the National Heart, Lung and Blood Institute. After the use of inclusion and exclusion criteria, the pre-and post-treatment volumes were used to visualize the effect of various orthodontics interventions. RESULTS: A total of 48 studies were included in this review and none of which were RCTs. The quality of all included studies was assessed as medium. Overall, there is a tendency for an increase in airway volumes after various orthodontic interventions, except for studies concerning extraction therapy with fixed appliances in adults, in which both increases and decreases in airway volumes have been reported. CONCLUSION: Orthodontic treatment by growth modification and non-extraction therapy with fixed appliances, regardless of the malocclusion, generally showed positive effects on the airway volume. Orthodontic treatment in combination with extractions does not provide an unambiguous insight. A consensus on the methodology of the airway measurement and nomenclature is urgently needed in order to gain insight into the effect of different interventions on three-dimensional airway changes. CLINICAL RELEVANCE: Various orthodontic treatments do not negatively influence the upper airway volume. However, extraction therapy in adults should be chosen with caution, especially in subjects belonging to a group susceptible to airway obstruction.

ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer.

c-Ros oncogene 1, receptor tyrosine kinase (ROS1) genomic rearrangements have been reported previously in rare cases of colorectal cancer (CRC), yet little is known about the frequency, molecular characteristics, and therapeutic vulnerabilities of ROS1-driven CRC. We analyzed a clinical dataset of 40 589 patients with CRC for ROS1 genomic rearrangements and their associated genomic characteristics (Foundation Medicine, Inc [FMI]). We moreover report the disease course and treatment response of an index patient with ROS1-rearranged metastatic CRC. ROS1 genomic rearrangements were identified in 34 (0.08%) CRC samples. GOPC-ROS1 was the most common ROS1 fusion identified (11 samples), followed by TTC28-ROS1 (3 samples). Four novel 5' gene partners of ROS1 were identified (MCM9, SRPK1, EPHA6, P4HA1). Contrary to previous reports on fusion-positive CRC, ROS1-rearrangements were found exclusively in microsatellite stable (MSS) CRCs. KRAS mutations were significantly less abundant in ROS1-rearranged vs ROS1 wild type cases. The index patient presented with chemotherapy-refractory metastatic right-sided colon cancer harboring GOPC-ROS1. Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response. After 15 months on crizotinib disseminated tumor progression occurred and KRAS Q61H emerged in tissue and liquid biopsies. ROS1 rearrangements define a small, yet therapeutically actionable molecular subgroup of MSS CRC. In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials.

The Co-mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion-Driven Cholangiocarcinoma.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion-positive ICC. Response rates of up to 35% indicate that FGFR-targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or response to FGFR-targeted therapies in patients with ICC. APPROACH AND RESULTS: In this study, we use an autochthonous murine model of ICC to demonstrate that FGFR2 fusions are potent drivers of malignant transformation. Furthermore, we provide preclinical evidence that the co-mutational spectrum acts not only as an accelerator of tumor development, but also modifies the response to targeted FGFR inhibitors. Using pharmacologic approaches and RNA-interference technology, we delineate that Kirsten rat sarcoma oncogene (KRAS)-activated mitogen-activated protein kinase signaling causes primary resistance to FGFR inhibitors in FGFR2 fusion-positive ICC. The translational relevance is supported by the observation that a subset of human FGFR2 fusion patients exhibits transcriptome profiles reminiscent of KRAS mutant ICC. Moreover, we demonstrate that combination therapy has the potential to overcome primary resistance and to sensitize tumors to FGFR inhibition. CONCLUSIONS: Our work highlights the importance of the co-mutational spectrum as a significant modifier of response in tumors that harbor potent oncogenic drivers. A better understanding of the genetic underpinnings of resistance will be pivotal to improve biomarker-guided patient selection and to design clinically relevant combination strategies.

Comparative evaluation of somatostatin and CXCR4 receptor expression in different types of thyroid carcinoma using well-characterised monoclonal antibodies.

BACKGROUND: Papillary and follicular thyroid carcinomas can be treated surgically and with radioiodine therapy, whereas therapeutic options for advanced stage IV medullary and for anaplastic tumours are limited. Recently, somatostatin receptors (SSTs) and the chemokine receptor CXCR4 have been evaluated for the treatment of thyroid carcinomas, however, with contradictory results. METHODS: The expression of the five SSTs and of CXCR4 was assessed in 90 samples from 56 patients with follicular, papillary, medullary, or anaplastic thyroid carcinoma by means of immunohistochemistry using well-characterised monoclonal antibodies. The stainings were evaluated using the Immunoreactivity Score (IRS) and correlated to clinical data. In order to further substantiate the immunohistochemistry results, in serial sections of a subset of the samples receptor expression was additionally examined at the mRNA level using qRT-PCR. RESULTS: Overall, SST and CXCR4 protein expression was low in all four entities. In single cases, however, very high IRS values for SST2 and CXCR4 were observed. SST2 was the most frequently expressed receptor, found in 38% of cases, followed by SST5 and SST4, found in 14 and 9% of tumours, respectively. SST1 and SST3 could not be detected to any significant extent. CXCR4 was present in 12.5% of medullary and 25% of anaplastic carcinomas. Expression SST3, SST4, SST5 and CXCR4 was positively correlated with expression of the proliferation marker Ki-67. Additionally, a negative interrelationship between SST4 or SST5 expression and patient survival and a positive association between SST3 expression and tumour diameter were observed. qRT-PCR revealed a similar receptor expression pattern to that seen at the protein level. However, probably due to the low overall expression, no correlation was found for the SSTs or the CXCR4 between the IRS and the mRNA values. CONCLUSIONS: SST- or CXCR4-based diagnostics or therapy in thyroid carcinomas should not be considered in general but may be feasible in single cases with high levels of expression of these receptors.

Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects.

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.

Assessment of G Protein-Coupled Oestrogen Receptor Expression in Normal and Neoplastic Human Tissues Using a Novel Rabbit Monoclonal Antibody.

In addition to the classical oestrogen receptors, ERα and ERß, a G protein-coupled oestrogen receptor (GPER) has been identified that primarily mediates the rapid, non-genomic signalling of oestrogens. Data on GPER expression at the protein level are contradictory; therefore, the present study was conducted to re-evaluate GPER expression by immunohistochemistry to obtain broad GPER expression profiles in human non-neoplastic and neoplastic tissues, especially those not investigated in this respect so far. We developed and thoroughly characterised a novel rabbit monoclonal anti-human GPER antibody, 20H15L21, using Western blot analyses and immunocytochemistry. The antibody was then applied to a large series of formalin-fixed, paraffin-embedded human tissue samples. In normal tissue, GPER was identified in distinct cell populations of the cortex and the anterior pituitary; islets and pancreatic ducts; fundic glands of the stomach; the epithelium of the duodenum and gallbladder; hepatocytes; proximal tubules of the kidney; the adrenal medulla; and syncytiotrophoblasts and decidua cells of the placenta. GPER was also expressed in hepatocellular, pancreatic, renal, and endometrial cancers, pancreatic neuroendocrine tumours, and pheochromocytomas. The novel antibody 20H15L21 will serve as a valuable tool for basic research and the identification of GPER-expressing tumours during histopathological examinations.

Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment.

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome­rate of ypT0 status­to justify subsequent prospective validation within the "BladderBRIDGister". Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal−Wallis, Mann−Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.

First clinical results of 1-year follow-up of the femoral neck system for internal fixation of femoral neck fractures.

BACKGROUND: Closed reduction and internal fixation (CRIF) is the preferred treatment to retain the native joint and maintain optimal functionality in femoral neck fractures. Sliding hip screw (SHS) and cannulated hip screws (CHS) are established CRIF options. SHS offer high biomechanical stability, whereas CHS are minimally invasive. These established systems have a 17-21% failure rate. The Femoral neck system (FNS) was recently developed to combine the advantages of both predecessors. The aim of this study was to describe the first clinical experience with this novel implant with special emphasis on the safety and efficacy. METHODS: During a 1-year period all patients in our level-2 trauma centre with a FNF indicated for CRIF were treated using the FNS and evaluated at 2, 6, 12 weeks, 6 months and 1 year postoperatively using patient and fracture characteristics, surgical notes and radiographic imaging. RESULTS: Thirty-four patients were included, mean age was 63 years (SD 8), 58.2% was female. Fractures were classified as Pauwels I (n = 10), Pauwels II (n = 15), Pauwels III (n = 9), Garden I (n = 1), Garden II (n = 17), Garden III (n = 12) and Garden IV (n = 4). Eight reoperations were reported after 1-year follow-up; osteosyntheses failed in 6 patients due to avascular necrosis (n = 4) and cut-out (n = 2). In two patients the implant was removed due to inexplicable pain. Age (< 65 years) was related to lower risk for failure. There was a trend for females having more failures. CONCLUSION: This study indicates that the FNS is a potential safe and effective CRIF modality. Age (< 65 years) is an important factor to keep in mind when selecting patients for CRIF as it is related to lower risk for failure. Future long-term follow-up studies with larger populations should indicate if functional results and risk factors for failure are comparable to SHS or CHS.

Face-selective responses in combined EEG/MEG recordings with fast periodic visual stimulation (FPVS).

Fast periodic visual stimulation (FPVS) allows the recording of objective brain responses of human face categorization (i.e., generalizable face-selective responses) with high signal-to-noise ratio. This approach has been successfully employed in a number of scalp electroencephalography (EEG) studies but has not been used with magnetoencephalography (MEG) yet, let alone with combined MEG/EEG recordings and distributed source estimation. Here, we presented various natural images of faces periodically (1.2 Hz) among natural images of objects (base frequency 6 Hz) whilst recording simultaneous EEG and MEG in 15 participants. Both measurement modalities showed face-selective responses at 1.2 Hz and harmonics across participants, with high and comparable signal-to-noise ratio (SNR) in about 3 min of stimulation. The correlation of face categorization responses between EEG and two MEG sensor types was lower than between the two MEG sensor types, indicating that the two sensor modalities provide independent information about the sources of face-selective responses. Face-selective EEG responses were right-lateralized as reported previously, and were numerically but non-significantly right-lateralized in MEG data. Distributed source estimation based on combined EEG/MEG signals confirmed a more bilateral face-selective response in visual brain regions located anteriorly to the common response to all stimuli at 6 Hz and harmonics. Conventional sensor and source space analyses of evoked responses in the time domain further corroborated this result. Our results demonstrate that FPVS in combination with simultaneously recorded EEG and MEG may serve as an efficient localizer paradigm for human face categorization.

What can the hair tell us about COVID-19?

The novel viral pandemic coronavirus disease 2019 (COVID-19) has sparked uncertainties as to its origin, epidemiology and natural course. The study of the cutaneous manifestations of COVID-19 has evolved with the hope that they may be useful as markers for the disease, prognostication and pathogenic insights into the disease. With regard to the hair, clinicopathological correlations have remained elusive. More recently, androgenetic alopecia and grey hair have been proposed as cutaneous markers for elevated severity risk. So far, we have only observed postinfectious effluvium in a causal association with COVID-19. The onset and acuity of hair shedding depended on the clinical severity of disease. There was complete recovery of hair.

Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer.

BACKGROUND: Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19-9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. METHODS: Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19-9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. RESULTS: Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19-9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19-9 levels outperformed either individual marker. cfKRASmut outperformed CA 19-9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. CONCLUSIONS: Integrated analysis of cfKRASmut and CA 19-9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker's specific potential.