EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of ...79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer ...2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.
Summary
Background
With the expanding list of medications available to treat patients with inflammatory bowel disease (IBD), it is important to recognise adverse events, including those involving the ...skin. Dermatological adverse events may be confused with extra‐intestinal manifestations of IBD.
Aim
To review drug‐related dermatological manifestations associated with immunosuppressive and anti‐tumour necrosis factor (anti‐TNF) therapy.
Methods
The literature was searched on PubMed for dermatological adverse events in IBD.
Results
Present thiopurine exposure was associated with a 5.9‐fold 95% confidence interval (CI), 2.1–16.4 increased risk of developing non‐melanoma skin cancer (NMSC). The peak incidence is highest in Caucasians over the age of 65 years with crude incidence rates of 4.0 and 5.7/1000 patient‐years for present and previous use. In anti‐TNF‐exposed subjects, drug‐induced lupus was reported in 1% of the cases and a psoriatic rash in up to 3% of the cases. Anti‐TNF monotherapy increases the risk of NMSC ~2‐fold to a rate of 0.5 cases per 1000 person‐years. Cutaneous lymphomas have been rarely reported in subjects on thiopurine or anti‐TNF drug monotherapy. Combination therapy seems to have an additive effect on the risk of developing NMSC and lymphoma.
Conclusions
Physicians need to be aware of the wide spectrum of dermatological complications of immunosuppressive and anti‐TNF therapy in IBD, especially psoriasis and non‐melanoma skin cancer. Vigilance and regular screening for non‐melanoma skin cancer is recommended. Case discussions between gastroenterologists and dermatologists should be undertaken to best manage dermatological adverse events.
Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated ...a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed.
Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8–1.1Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point.
A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P<0.001) and PFS, by univariate (P<0.001) and multivariate analysis (P<0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18months) while the median PFS for TMBlow was 2months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point.
TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
There have been limited data on the risk of onward transmission from individuals with Omicron variant infections who return to work after a 5-day isolation.
To evaluate the risk of transmission from ...healthcare workers (HCWs) with Omicron variant who returned to work after a 5-day isolation and the viable-virus shedding kinetics.
This investigation was performed in a tertiary care hospital, Seoul, South Korea. In a secondary transmission study, we retrospectively reviewed the data of HCWs confirmed as COVID-19 from March 14th to April 3rd, 2022 in units with five or more COVID-19-infected HCWs per week. In the viral shedding kinetics study, HCWs with Omicron variant infection who agreed with daily saliva sampling were enrolled between February and March, 2022.
Of the 248 HCWs who were diagnosed with COVID-19 within 5 days of the return of an infected HCW, 18 (7%) had contact with the returned HCW within 1–5 days after their return. Of these, nine (4%) had an epidemiologic link other than with the returning HCW, and nine (4%) had contact with the returning HCW, without any other epidemiologic link. In the study of the kinetics of virus shedding (N = 32), the median time from symptom onset to negative conversion of viable virus was four days (95% confidence interval: 3–5).
Our data suggest that the residual risk of virus transmission after 5 days of isolation following diagnosis or symptom onset is low.
Abstract Background Context Clinicians regard lumbar lordotic curvature (LLC) with respect to low back pain (LBP) in a contradictory fashion. The time-honored point of view is that LLC itself, or its ...increment, causes LBP. On the other hand, recently, the biomechanical role of LLC has been emphasized, and loss of lordosis is considered a possible cause of LBP. The relationship between LLC and LBP has immense clinical significance, because it serves as the basis of therapeutic exercises for treating and preventing LBP. Purpose This study aimed to (1) determine the difference in LLC in those with and without LBP and (2) investigate confounding factors that might affect the association between LLC and LBP. Study Design Systematic review and meta-analysis. Patient Sample The inclusion criteria consisted of observational studies that included information on lumbar lordotic angle (LLA) assessed by radiological image, in both patients with LBP and healthy controls. Studies solely involving pediatric populations, or addressing spinal conditions of nondegenerative causes, were excluded. Methods A systematic electronic search of Medline, Embase, Cochrane Library, CINAHL, Scopus, PEDro, and Web of Science using terms related to lumbar alignment and Boolean logic was performed: (lumbar lordo*) or (lumbar alignment) or (sagittal alignment) or (sagittal balance). Standardized mean differences (SMD) and 95% confidence intervals (CI) were estimated, and chi-square and I2 statistics were used to assess within-group heterogeneity by random effects model. Additionally, the age and gender of participants, spinal disease entity, and the severity and duration of LBP were evaluated as possible confounding factors. Results A total of 13 studies consisting of 796 patients with LBP and 927 healthy controls were identified. Overall, patients with LBP tended to have smaller LLA than healthy controls. However, the studies were heterogeneous. In the meta-regression analysis, the factors of age, severity of LBP, and spinal disease entity were revealed to contribute significantly to variance between studies. In the subgroup analysis of the five studies that compared patients with disc herniation or degeneration with healthy controls, patients with LBP had smaller LLA (SMD: −0.94, 95% CI: −1.19 to −0.69), with sufficient homogeneity based on significance level of .1 (I2 =45.7%, p=.118). In the six age-matched studies, patients with LBP had smaller LLA than healthy controls (SMD: −0.33, 95% CI: −0.46 to −0.21), without statistical heterogeneity (I2 =0%, p=.916). Conclusions This meta-analysis demonstrates a strong relationship between LBP and decreased LLC, especially when compared with age-matched healthy controls. Among specific diseases, LBP by disc herniation or degeneration was shown to be substantially associated with the loss of LLC.
Summary Background Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, ...non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. Methods In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov , NCT00939770. Findings 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1–21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1–6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). Interpretation The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. Funding Pfizer and National Cancer Institute grant to the Children's Oncology Group.
Trade in pangolins is illegal, and yet tons of their scales and products are seized at various ports. These large seizures are challenging to process and comprehensively genotype for upstream ...provenance tracing and species identification for prosecution. We implemented a scalable DNA barcoding pipeline in which rapid DNA extraction and MinION sequencing were used to genotype a substantial proportion of pangolin scales subsampled from 2 record shipments seized in Singapore in 2019 (37.5 t). We used reference sequences to match the scales to phylogeographical regions of origin. In total, we identified 2346 cytochrome b (cytb) barcodes of white‐bellied (Phataginus tricuspis) (from 1091 scales), black‐bellied (Phataginus tetradactyla) (227 scales), and giant (Smutsia gigantea) (1028 scales) pangolins. Haplotype diversity was higher for P. tricuspis scales (121 haplotypes, 66 novel) than that for P. tetradactyla (22 haplotypes, 15 novel) and S. gigantea (25 haplotypes, 21 novel) scales. Of the novel haplotypes, 74.2% were likely from western and west‐central Africa, suggesting potential resurgence of poaching and newly exploited populations in these regions. Our results illustrate the utility of extensively subsampling large seizures and outline an efficient molecular approach for rapid genetic screening that should be accessible to most forensic laboratories and enforcement agencies.
Revelación de la magnitud de la caza furtiva del pangolín africano mediante el genotipo extenso de nanoporos de ADN de escamas incautadas
Resumen
Aunque el mercado de pangolines es ilegal, se incautan toneladas de sus escamas y productos derivados en varios puertos comerciales. Es un reto procesar estas magnas incautaciones y obtener el genotipo completo para usarlo en la trazabilidad logística ascendente e identificación de la especie y así imponer sanciones. Implementamos una canalización escalable del código de barras de ADN en el cual usamos la extracción rápida de ADN y la secuenciación MinION para obtener el genotipo de una proporción sustancial de las escamas de pangolín submuestreadas en dos cargamentos incautados en 2019 en Singapur (37.5 t). Usamos secuencias referenciales para emparejar las escamas con las regiones filogeográficas de origen. Identificamos en total 2,346 códigos de citocromo b (cytb) del pangolín de vientre blanco (Phataginus tricuspis) (de 1,091 escamas), de vientre negro (P. tetradactyla) (227 escamas) y del pangolín gigante (Smutsia gigantea) (1,028 escamas). La diversidad de haplotipos fue mayor en las escamas de P. tricuspis (121 haplotipos, 66 nuevos) que en las de P. tetradactyla (22 haplotipos, 15 nuevos) y S. gigantea (25 haplotipos, 21 nuevos). De los haplotipos nuevos, el 74.2% probablemente provenía del occidente y centro‐occidente de África, lo que sugiere un resurgimiento potencial de la caza furtiva y poblaciones recién explotadas en estas regiones. Nuestros resultados demuestran la utilidad de submuestrear extensivamente las grandes incautaciones y esboza una estrategia molecular eficiente para un análisis genético rápido que debería ser accesible para la mayoría de los laboratorios forenses y las autoridades de aplicación.
This study proposes a novel optical fiber Bragg grating (FBG)-based load cell sensor using 3-D printing technology. It explores the impact of the infill density and pattern on the FBG's temperature ...and mechanical strain sensitivity. Two FBGs were used, one for strain measurement, FBG L, and the other for temperature compensation, FBG T. Conducted measurements show that the strain-sensitive FBG L and strain-free FBG T exhibited a similar average temperature sensitivity value of around 10.5 pm/°C with a good linearity value of 99.92%. This will also allow the unstrained FBG T to effectively compensate for FBG L's temperature changes during load measurement. Under varied load conditions, load cell sensors with lower infill density, such as 20%, displayed more significant average wavelength shift and increased strain sensitivities compared to those with higher infill density, such as 80%, due to having more voids and hollow sections within its actuator. This facilitates easier deformation, thus inducing more significant stretching on FBG L. Regarding the infill pattern, the gyroid pattern outperformed the tri-hexagon in both average wavelength shift and strain responses, showing its suitability for precise measurements under diverse loads. Therefore, this work demonstrates the critical role of the infill density and pattern in the performance of an efficient load cell sensor using FBGs.
Aims/hypothesis
The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the ...susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.
Methods
Rat insulin promoter (RIP)-
Cre
+
;autophagy-related 7 (
Atg7
)
F/W
mice were bred with
ob/w
mice to derive RIP-
Cre
+
;
Atg7
F/F
-
ob/ob
mice and to induce ER stress in vivo.
GFP-LC3
+
-
ob/ob
mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.
Results
Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with
ob/ob
mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.
Conclusions/interpretation
These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.
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