In silico quantification of cell proportions from mixed-cell transcriptomics data (deconvolution) requires a reference expression matrix, called basis matrix. We hypothesize that matrices created ...using only healthy samples from a single microarray platform would introduce biological and technical biases in deconvolution. We show presence of such biases in two existing matrices, IRIS and LM22, irrespective of deconvolution method. Here, we present immunoStates, a basis matrix built using 6160 samples with different disease states across 42 microarray platforms. We find that immunoStates significantly reduces biological and technical biases. Importantly, we find that different methods have virtually no or minimal effect once the basis matrix is chosen. We further show that cellular proportion estimates using immunoStates are consistently more correlated with measured proportions than IRIS and LM22, across all methods. Our results demonstrate the need and importance of incorporating biological and technical heterogeneity in a basis matrix for achieving consistently high accuracy.
Background:
Zoledronic acid every 4 weeks (Q4wk) reduces the incidence of skeletal-related events (SREs) in patients with metastatic lung cancer. Lung cancer patients were excluded from ...extended-interval dosing trials (every 12 weeks Q12wk) that demonstrated noninferiority of the 2 dosing schemes. To date, the optimal dosing of zoledronic acid in metastatic lung cancer remains unknown.
Objective:
To determine whether zoledronic acid dosed Q12wk is similar to Q4wk dosing for prevention of SRE in patients with metastatic lung cancer.
Methods:
A retrospective analysis was performed in patients with non–small-cell lung cancer and small-cell lung cancer with bone metastases who received Q12wk and Q4wk zoledronic acid. The primary outcome was incidence of SRE at 1 year. Secondary analyses included time to first SRE, overall survival (OS), incidence of osteonecrosis of the jaw (ONJ), kidney dysfunction, and hypocalcemia.
Results:
A total of 34 patients received Q12wk and 46 patients received Q4wk zoledronic acid. Incidence of SRE at 1 year (Q12wk, 23.5%, vs Q4wk, 23.9%; 95% CI = −0.184 to 0.192; P = 0.968) and median time to SRE (not reached for either cohort; P = 0.530) did not differ. The Q12wk cohort had longer median OS (24.00 vs 8.97 months; P = 0.022). There were no differences in incidence of ONJ, kidney dysfunction, and hypocalcemia.
Conclusion and Relevance:
This is the first report examining extended-interval dosing of zoledronic acid in metastatic lung cancer. Incidence and time to SRE at 1 year were similar. This extended-interval dosing may be safe and reasonable for patients with lung cancer with bone metastases.
Chinese Communist monocultural policies, notably the re-education camps for the Uyghurs in Xinjiang, have recently been condemned for violating human rights. In response to critics, the Chinese ...Communist Party frequently replied that one should not impose Western concepts of democracy, liberty, and human rights on the Chinese people. Nevertheless, instead of introducing Western philosophies criticizing the current Chinese Communist monoculturalism; with the help of a modern reinterpretation of the Classic of Rites, this paper aims to construct a Confucian Multiculturalism and argues that: (1) the Classic of Rites explicitly warned against cultural assimilations of “barbarians” into the “civilized” Empire, (2) the Classic of Rites acknowledges cultural diversities, and (3) although the Classic of Rites does not explain clearly why the imperial court should tolerate cultural diversities, a Kantian reinterpretation of the Chinese concept of 敬 Jing implies the respects for minority rights. In doing so, this paper formulates Confucian Multiculturalism as a new model of the Chinese philosophy of culture which asserts cultural diversity.
The tumour suppressor alternative reading frame (ARF) is one of the most frequently mutated proteins in human cancer. It has been well established that ARF is able to stabilize and activate p53 by ...directly inhibiting Mdm2. ARF-mediated p53 activation in response to oncogenic stress is thought to be an important determinant of protection against cancer. However, little is known regarding the control of ARF in cells. Here, we show that Siva1 is a specific E3 ubiquitin ligase of ARF. Siva1 physically interacts with ARF both in vitro and in vivo. Through direct interaction, Siva1 promotes the ubiquitination and degradation of ARF, which in turn affects the stability of p53. Functionally, Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53-dependent manner. Our results uncover a novel regulatory mechanism for the control of ARF stability, thereby revealing an important function of Siva1 in the regulation of the ARF-Mdm2-p53 pathway.
Evidence supports use of teleconsultation for improving patient access to dermatology. However, little is known about the quality of rapidly expanding direct-to-consumer (DTC) telemedicine websites ...and smartphone apps diagnosing and treating skin disease.
To assess the performance of DTC teledermatology services.
Simulated patients submitted a series of structured dermatologic cases with photographs, including neoplastic, inflammatory, and infectious conditions, using regional and national DTC telemedicine websites and smartphone apps offering services to California residents.
Choice of clinician, transparency of credentials, clinician location, demographic and medical data requested, diagnoses given, treatments recommended or prescribed, adverse effects discussed, care coordination.
We received responses for 62 clinical encounters from 16 DTC telemedicine websites from February 4 to March 11, 2016. None asked for identification or raised concerns about pseudonym use or falsified photographs. During most encounters (42 68%), patients were assigned a clinician without any choice. Only 16 (26%) disclosed information about clinician licensure, and some used internationally based physicians without California licenses. Few collected the name of an existing primary care physician (14 23%) or offered to send records (6 10%). A diagnosis or likely diagnosis was proffered in 48 encounters (77%). Prescription medications were ordered in 31 of 48 diagnosed cases (65%), and relevant adverse effects or pregnancy risks were disclosed in a minority (10 of 31 32% and 6 of 14 43%, respectively). Websites made several correct diagnoses in clinical scenarios where photographs alone were adequate, but when basic additional history elements (eg, fever, hypertrichosis, oligomenorrhea) were important, they regularly failed to ask simple relevant questions and diagnostic performance was poor. Major diagnoses were repeatedly missed, including secondary syphilis, eczema herpeticum, gram-negative folliculitis, and polycystic ovarian syndrome. Regardless of the diagnoses given, treatments prescribed were sometimes at odds with existing guidelines.
Telemedicine has potential to expand access to high-value health care. Our findings, however, raise concerns about the quality of skin disease diagnosis and treatment provided by many DTC telemedicine websites. Ongoing expansion of health plan coverage of these services may be premature. Until improvements are made, patients risk using health care services that lack transparency, choice, thoroughness, diagnostic and therapeutic quality, and care coordination. We offer several suggestions to improve the quality of DTC telemedicine websites and apps and avoid further growth of fragmented, low-quality care.
Animal migration contributes largely to the seasonal dynamics of High Arctic ecosystems, linking distant habitats and impacting ecosystem structure and function. In polar deserts, Arctic hares are ...abundant herbivores and important components of food webs. Their annual migrations have long been suspected, but never confirmed. We tracked 25 individuals with Argos satellite telemetry to investigate the existence of migration in a population living at Alert (Ellesmere Island, Nunavut, Canada). During fall, 21 hares undertook directional, long-distance movements in a southwestern direction towards Lake Hazen. Daily movement rates averaged 1.3 ± 0.5 km, 4.3 ± 1.6 km, and 1.7 ± 0.9 km before, during, and after relocation, respectively. Straight-line and minimum cumulative distances traveled averaged 98 ± 18 km (range: 72-148 km) and 198 ± 62 km (range: 113-388 km), respectively. This is the first report of large-scale seasonal movements in Arctic hares and, surprisingly, in any lagomorph species. These movements may be part of an annual migratory pattern. Our results redefine our understanding of the spatial ecology of Arctic hares, demonstrate unsuspected mobility capacities in lagomorphs, and open new perspectives regarding the ecological dynamics of the northern polar deserts.
The use of remote sensing for developing land cover maps in the Arctic has grown considerably in the last two decades, especially for monitoring the effects of climate change. The main challenge is ...to link information extracted from satellite imagery to ground covers due to the fine-scale spatial heterogeneity of Arctic ecosystems. There is currently no commonly accepted methodological scheme for high-latitude land cover mapping, but the use of remote sensing in Arctic ecosystem mapping would benefit from a coordinated sharing of lessons learned and best practices. Here, we aimed to produce a highly accurate land cover map of the surroundings of the Canadian Forces Station Alert, a polar desert on the northeastern tip of Ellesmere Island (Nunavut, Canada) by testing different predictors and classifiers. To account for the effect of the bare soil background and water limitations that are omnipresent at these latitudes, we included as predictors soil-adjusted vegetation indices and several hydrological predictors related to waterbodies and snowbanks. We compared the results obtained from an ensemble classifier based on a majority voting algorithm to eight commonly used classifiers. The distance to the nearest snowbank and soil-adjusted indices were the top predictors allowing the discrimination of land cover classes in our study area. The overall accuracy of the classifiers ranged between 75 and 88%, with the ensemble classifier also yielding a high accuracy (85%) and producing less bias than the individual classifiers. Some challenges remained, such as shadows created by boulders and snow covered by soil material. We provide recommendations for further improving classification methodology in the High Arctic, which is important for the monitoring of Arctic ecosystems exposed to ongoing polar amplification.
We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue.
Mice were treated with the pan-Notch ...inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors.
Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth.
Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach.
Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC ...produces the granulocyte–macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan–Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months mos (range 1.0–58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4–NR mos) and 2.8 mos (95% CI, 0.7–4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6–NR mos) and 2.8 mos (95% CI, 0.7–4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval CI, 4.1–not reached NR mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0–NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4–26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7–NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.
The standard of care for patients with locally advanced cervical cancer is definitive chemoradiation followed by a brachytherapy boost. This review describes the current status and future directions ...of image-guided adaptive brachytherapy for locally advanced cervical cancer.
A systematic search of the PubMed and Clinicaltrials.gov databases was performed, focusing on studies published within the last 10 years. The search queried "cervical cancer AND image-guided brachytherapy OR magnetic resonance imaging (MRI) OR adaptive brachytherapy".
The retroEMBRACE and EMBRACE-I trials have established the use of MRI as the standard imaging modality for brachytherapy application and planning. Quantitative imaging and radiomics have the potential to improve outcomes, with three ongoing prospective studies examining the use of radiomics to further risk-stratify patients and personalize brachytherapy. Another active area of investigation includes utilizing the superior soft tissue contrast provided by MRI to increase the dose per fraction and decrease the number of fractions needed for brachytherapy, with several retrospective studies demonstrating the safety and feasibility of three-fraction courses. For developing countries with limited access to MRI, trans-rectal ultrasound (TRUS) appears to be an effective alternative, with several retrospective studies demonstrating improved target delineation with the use of TRUS in conjunction with CT guidance.
Further investigation is needed to continue improving outcomes for patients with locally advanced cervical cancer treated with image-guided brachytherapy.
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