Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic ...plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation.
Summary Background The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant ...chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. Methods In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3–4N0) or III (ypTany N1–2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2 on days 1–5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 , and fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov , number NCT00807911. Findings Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4–50·6). 3-year disease-free survival was 71·6% (95% CI 64·6–78·6) in the FOLFOX group and 62·9% (55·4–70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434–0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 26% of 149 patients in the fluorouracil plus leucovorin group vs 52 36% of 146 patients in the FOLFOX group), leucopenia (eight 5% vs 12 8%), febrile neutropenia (four 3% vs one <1%), diarrhoea (four 3% vs two 1%), and nausea (one <1% vs two 1%). Interpretation Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. Funding Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).
Arabidopsis thaliana homeobox 12 (ATHB12), a homeodomain‐leucine zipper class I (HD‐Zip I) gene, is highly expressed in leaves and stems, and induced by abiotic stresses, but its role in development ...remains obscure. To understand its function during plant development, we studied the effects of loss and gain of function. Expression of ATHB12 fused to the EAR‐motif repression domain (SRDX) – P₃₅S::ATHB12SRDX (A12SRDX) and PATHB₁₂::ATHB12SRDX – slowed both leaf and root growth, while the growth of ATHB12‐overexpressing seedlings (A12OX) was accelerated. Microscopic examination revealed changes in the size and number of leaf cells. Ploidy was reduced in A12SRDX plants, accompanied by decreased cell expansion and increased cell numbers. By contrast, cell size was increased in A12OX plants, along with increased ploidy and elevated expression of cell cycle switch 52s (CCS52s), which are positive regulators of endoreduplication, indicating that ATHB12 promotes leaf cell expansion and endoreduplication. Overexpression of ATHB12 led to decreased phosphorylation of Arabidopsis thaliana ribosomal protein S6 (AtRPS6), a regulator of cell growth. In addition, induction of ATHB12 in the presence of cycloheximide increased the expression of several genes related to cell expansion, such as EXPANSIN A10 (EXPA10) and DWARF4 (DWF4). Our findings strongly suggest that ATHB12 acts as a positive regulator of endoreduplication and cell growth during leaf development.
Most existing electrocardiogram (ECG) feature extraction methods rely on rule-based approaches. It is difficult to manually define all ECG features. We propose an unsupervised feature learning method ...using a convolutional variational autoencoder (CVAE) that can extract ECG features with unlabeled data. We used 596,000 ECG samples from 1,278 patients archived in biosignal databases from intensive care units to train the CVAE. Three external datasets were used for feature validation using two approaches. First, we explored the features without an additional training process. Clustering, latent space exploration, and anomaly detection were conducted. We confirmed that CVAE features reflected the various types of ECG rhythms. Second, we applied CVAE features to new tasks as input data and CVAE weights to weight initialization for different models for transfer learning for the classification of 12 types of arrhythmias. The f1-score for arrhythmia classification with extreme gradient boosting was 0.86 using CVAE features only. The f1-score of the model in which weights were initialized with the CVAE encoder was 5% better than that obtained with random initialization. Unsupervised feature learning with CVAE can extract the characteristics of various types of ECGs and can be an alternative to the feature extraction method for ECGs.
Summary Background Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes ...is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. Methods The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18–80 years) with cT3N0–2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00470951. Findings We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (–6·7%, 95% CI −15·8 to 2·4; p<0·0001). 25 (15%) patients died in the open group and 20 (12%) died in the laparoscopic group. No deaths were treatment related. Interpretation Our results show that laparoscopic resection for locally advanced rectal cancer after preoperative chemoradiotherapy provides similar outcomes for disease-free survival as open resection, thus justifying its use. Funding National Cancer Center, South Korea.
Drug-induced QT prolongation is one of the most common side effects of drug use and can cause fatal outcomes such as sudden cardiac arrest. This study adopts the data-driven approach to assess the QT ...prolongation risk of all the frequently used drugs in a tertiary teaching hospital using both standard 12-lead ECGs and intensive care unit (ICU) continuous ECGs. We used the standard 12-lead ECG results (n = 1,040,752) measured in the hospital during 1994-2019 and the continuous ECG results (n = 4,835) extracted from the ICU's patient-monitoring devices during 2016-2019. Based on the drug prescription frequency, 167 drugs were analyzed using 12-lead ECG data under the case-control study design and 60 using continuous ECG data under the retrospective cohort study design. Whereas the case-control study yielded the odds ratio, the cohort study generated the hazard ratio for each candidate drug. Further, we observed the possibility of inducing QT prolongation in 38 drugs in the 12-lead ECG analysis and 7 drugs in the continuous ECG analysis. The seven drugs (vasopressin, vecuronium, midazolam, levetiracetam, ipratropium bromide, nifedipine, and chlorpheniramine) that showed a significantly higher risk of QT prolongation in the continuous ECG analysis were also identified in the 12-lead ECG data analysis. The use of two different ECG sources enabled us to confidently assess drug-induced QT prolongation risk in clinical practice. In this study, seven drugs showed QT prolongation risk in both study designs.
Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with ...high-dose ABX and enzyme replacement therapy (ERT) in nGD.
ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.
Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.
Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.
A new technique, electro‐hydrodynamic nanowire (e‐NW) lithography , is demonstrated for the rapid, inexpensive, and efficient fabrication of graphene nanorib bons (GNRs) on a large scale while ...simultaneously controlling the location and alignment of the GNRs. A series of interesting GNR architectures, including parallel lines, grids, ladders, and stars are produced. A sub‐10‐nm‐wide GNR is obtained to fabricate field‐effect transistors that show a room‐temperature on/off current ratio of ca. 70.
Last‐minute labeling: Mesoporous silica nanoparticles (MSNs) were modified with a very short half‐life fluorine‐18‐labeled azide radiotracer by a cycloaddition reaction after the MSNs had reached the ...tumor site in mice. The tumor could then be visualized successfully with positron emission tomography.
To evaluate the effective dose and patterns of recurrence after stereotactic body radiation therapy (SBRT) for hepatic metastases that arise from colorectal cancer.
A cohort of 70 patients with 103 ...colorectal liver metastases were treated with SBRT at a single institution. The prescribed doses were 45 to 60 Gy in 3 to 4 fractions, but these were modified according to the tolerance of the adjacent normal tissue. To allow for dose comparisons, a biological equivalent dose was calculated.
The median follow-up period was 34.2 months (range, 5.3-121.8 months). The 2-year overall survival and progression-free survival rates were 75% and 35%, respectively. In subgroups, the 2-year local control rates for biological equivalent dose ≤80 Gy (group 1), 100 to 112 Gy (group 2), and ≥132 Gy (group 3) were 52%, 83%, and 89%, respectively. Cox proportional hazards model revealed a significant difference between groups (hazard ratio 0.44, P=.03 for group 2; hazard ratio 0.17, P=.17 for group 3; P=.01 for total). The major pattern of failure was a new liver metastasis out of the SBRT field. There was no grade ≥3 toxicity.
Stereotactic body radiation therapy of liver metastases derived from colorectal cancer offers a locally effective treatment without significant complications. Longer local control can be expected if higher doses are used. Further studies will be needed to compare the efficacies of SBRT with those of surgical resection or radiofrequency ablation.
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