Most current methods for neuromodulation target the cortex. Approaches for inducing plasticity in subcortical motor pathways, such as the reticulospinal tract, could help to boost recovery after ...damage (e.g., stroke). In this study, we paired loud acoustic stimulation (LAS) with transcranial magnetic stimulation (TMS) over the motor cortex in male and female healthy humans. LAS activates the reticular formation; TMS activates descending systems, including corticoreticular fibers. Two hundred paired stimuli were used, with 50 ms interstimulus interval at which LAS suppresses TMS responses. Before and after stimulus pairing, responses in the contralateral biceps muscle to TMS alone were measured. Ten, 20, and 30 min after stimulus pairing ended, TMS responses were enhanced, indicating the induction of LTP. No long-term changes were seen in control experiments which used 200 unpaired TMS or LAS, indicating the importance of associative stimulation. Following paired stimulation, no changes were seen in responses to direct corticospinal stimulation at the level of the medulla, or in the extent of reaction time shortening by a loud sound (StartReact effect), suggesting that plasticity did not occur in corticospinal or reticulospinal synapses. Direct measurements in female monkeys undergoing a similar paired protocol revealed no enhancement of corticospinal volleys after paired stimulation, suggesting no changes occurred in intracortical connections. The most likely substrate for the plastic changes, consistent with all our measurements, is an increase in the efficacy of corticoreticular connections. This new protocol may find utility, as it seems to target different motor circuits compared with other available paradigms.
Induction of plasticity by neurostimulation protocols may be promising to enhance functional recovery after damage such as following stroke, but current protocols mainly target cortical circuits. In this study, we developed a novel paradigm which may generate long-term changes in connections between cortex and brainstem. This could provide an additional tool to modulate and improve recovery.
Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide ...useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to assess changes in British Non-arthroplasty Hip Register (NAHR) minimum dataset (MDS) patient-reported outcome measures (PROMs) after hip arthroscopy for femoroacetabular ...impingement (FAI) and define the relation between these and patient satisfaction. Secondary aims included exploring the impact of patient characteristics (age, sex, and social deprivation status) on MDS PROMs and satisfaction and determining the Net Promoter Score for hip arthroscopy for FAI.
Preoperative data were collected from the NAHR, and postoperative data were collected through the NAHR, by mail, and by telephone survey. Correlations between satisfaction, International Hip Outcome Tool 12 (iHOT-12), and EQ-5D scores were explored.
A consecutive series of 89 primary hip arthroscopy procedures for FAI in 88 patients is reported. Patients reported improvements in the iHOT-12 score (mean, 34.08; 95% confidence interval CI, 27.88 to 40.28; P < .001), EQ-5D index score (+0.124; 95% CI, 0.063 to 0.185; P < .001), and EQ-5D visual analog scale (VAS) (+4.49; 95% CI, –1.56 to 10.54; P = .061) after hip arthroscopy for FAI. Satisfaction was predicted by both change in iHOT-12 score (Spearman r rs = 0.54, P < .001) and absolute postoperative iHOT-12 score (rs = 0.78, P < .001), change in EQ-5D index score (rs = 0.42, P < .001) and absolute postoperative EQ-5D index score (rs = 0.70, P < .001), and change in EQ-5D VAS score (rs = 0.30, P = .012) and absolute postoperative EQ-5D VAS score (rs = 0.59, P < .001); and the strength of correlation was greater with the absolute postoperative score than with the change in score for all 3. Sex, age, and social deprivation status did not predict postoperative PROMs (P ≥ .15) or satisfaction (P ≥ .32). The postoperative iHOT-12 score correlated strongly with EQ-5D index (rs = 0.90, P < .001) and EQ-5D VAS (rs = 0.81, P < .001) scores. The Net Promoter Score for hip arthroscopy for FAI was 70.31.
This study showed significant improvements in hip-specific function (iHOT-12) and health-related quality of life (EQ-5D), as measured by the NAHR MDS, in patients undergoing hip arthroscopy for FAI. Satisfaction rates were high (75.7%) and correlated strongly with hip-specific and general health PROMs. Satisfied patients were more likely to be willing to undergo similar surgery in the future. Self-reported postoperative hip function correlated very strongly with general health-related quality of life.
Level IV, case series.
Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and ...acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
The incidence rate of lung adenocarcinoma (LUAD), the predominant histological subtype of lung cancer, is elevated in Asians, particularly in female nonsmokers. The mutation patterns in LUAD in ...Asians might be distinct from those in LUAD in whites.
We profiled 271 resected LUAD tumors (mainly stage I) to characterize the genomic landscape of LUAD in Asians with a focus on female nonsmokers.
Mutations in EGFR, KRAS, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), and BRAF; gene fusions involving anaplastic lymphoma receptor tyrosine kinase gene (ALK), ROS1, and ret proto-oncogene (RET); and Met Proto-Oncogene Tyrosine Kinase (MET) exon 14 skipping were the major drivers in LUAD in Asians, exhibiting mutually exclusive and differing prevalence from those reported in studies of LUAD in non-Asians. In addition, we identified a novel mutational signature of XNX (the mutated base N in the middle flanked by two identical bases at the 5′ and 3′ positions) that was overrepresented in LUAD tumors in nonsmokers and negatively correlated with the overall mutational frequency.
In this cohort, approximately 85% of individuals have known driver mutations (EGFR 59.4%, KRAS 7.4%, ALK 7.4%, ERBB2 2.6%, ROS1 2.2%, RET 2.2%, MET 1.8%, BRAF 1.1%, and NRAS 0.4%). Seventy percent of smokers and 90% of nonsmokers had defined oncogenic drivers matching the U.S. Food and Drug Administration–approved targeted therapies.
Gastric cancer (GC) is the second most common cause of cancer-related deaths. It is known to be a heterogeneous disease with several molecular and histological subtypes. Here we perform whole-genome ...sequencing of 49 GCs with diffuse (N=31) and intestinal (N=18) histological subtypes and identify three mutational signatures, impacting TpT, CpG and TpCpA/T nucleotides. The diffuse-type GCs show significantly lower clonality and smaller numbers of somatic and structural variants compared with intestinal subtype. We further divide the diffuse subtype into one with infrequent genetic changes/low clonality and another with relatively higher clonality and mutations impacting TpT dinucleotide. Notably, we discover frequent and exclusive mutations in Ephrins and SLIT/ROBO signalling pathway genes. Overall, this study delivers new insights into the mutational heterogeneity underlying distinct histologic subtypes of GC that could have important implications for future research in the diagnosis and treatment of GC.
Abstract
Background
To date, to our knowledge, there has not been a study on dermatological teaching in the preclinical years (usually the first 2 years of medical school), where the majority of ...learning takes place in the form of lectures and seminars. Near-peer teaching (NPT) involves students who are at least one academic year more senior imparting knowledge to junior students. The principles behind scaffolding are having a more experienced teacher to guide learning, breaking down learning into smaller tasks and helping to build interest in learning.
Objectives
To investigate the feasibility and effectiveness of NPT in scaffolding dermatological learning among preclinical-year medical students.
Methods
Near-peer teachers who are content experts in dermatology taught alongside conventional teaching with lecturers. We employed five quiz questions before and after the case launch lecture, where students were first exposed to dermatology. We also invited students to provide feedback using a questionnaire on NPT in dermatology at the end of the case 8 teaching week.
Results
In total, 74 students participated in the pre- and post-lecture quiz questions, and 47 completed feedback. There was overwhelmingly positive feedback towards NPT, and various learning theories can help explain the success of this project.
Conclusions
Preclinical students enjoy dermatological teaching with the involvement of suitable near-peers. With the professional barrier removed, students can better relate to near-peers (and vice versa). Helping students understand the relevance of dermatology in the clinical setting at an early stage and adopting learning tools such as mnemonics, summary tables, comparison tables and mapping teaching with the learning curriculum clearly helped students learn about dermatology.
Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. ...Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial-mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.
This paper describes the fabrication of 3D soft, inflatable structures from thin, 2D tiles fabricated from elastomeric polymers. The tiles are connected using soft joints that increase the surface ...area available for gluing them together, and mechanically reinforce the structures to withstand the tensile forces associated with pneumatic actuation. The ability of the elastomeric polymer to withstand large deformations without failure makes it possible to explore and implement new joint designs, for example “double‐taper dovetail joints,” that cannot be used with hard materials. This approach simplifies the fabrication of soft structures comprising materials with different physical properties (e.g., stiffness, electrical conductivity, optical transparency), and provides the methods required to “program” the response of these structures to mechanical (e.g., pneumatic pressurization) and other physical (e.g., electrical) stimuli. The flexibility and modularity of this approach is demonstrated in a set of soft structures that expanded or buckled into distinct, predictable shapes when inflated or deflated. These structures combine easily to form extended systems with motions dependent on the configurations of the selected components, and, when fabricated with electrically conductive tiles, electronic circuits with pneumatically active elements. This approach to the fabrication of hollow, 3D structures provides routes to new soft actuators.
3D structures fabricated from elastomeric tiles change shape when inflated or deflated. The pneumatic expansion or contraction of these structures is “programmed” by selecting tiles with different mechanical properties. Connecting these structures together provides a method to explore soft machines with 3D architectures. Structures including electrically conductive tiles increase the designs and functions possible in soft machines.
To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models.
...Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (
= 1) trial.
Consistent with clinical results, cetuximab was efficacious in wild-type
and
PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored
or
mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that
and
mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a
value of 0.01 compared with cetuximab alone. In 12 models with
mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44
mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition.
MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a
or
mutation.
.
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