Background Cutaneous melanoma (CM) incidence rates continue to increase, and the reasons are unknown. Previously, we reported a unique age-specific gender difference in melanoma that suggested additional causes other than solar UV radiation. Objective This study attempted to understand whether and how UV radiation differentially impacts the CM incidence in men and women. Methods CM data and daily UV index (UVI) from 31 cancer registries were collected for association analysis. A second dataset from 42 states of the U.S.A. was used for validation. Results There was no association between log-transformed female CM rates and levels of UVI but there was a significant association between male rates and UVI and a significant association between overall rates and UVI. The 5 year age-specific rate-UVI association levels (represented by Pearson’s coefficient ρ) increased with age in men, but age-specific ρ levels remained low and unchanged in women. The significant rate-UVI association in men and non-association in women was validated in the US white population. Limitations Confounders including temperature and latitude are difficult to separate from UVI Conclusions: Ambient UVI appears to be associated with melanoma incidence in males but not in females.
Background Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. Methods The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Results Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors. Conclusions The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell ...
Purpose In the Indonesian health‐care system, nurses and midwives often serve as the primary health‐care providers due to physician shortages. Seeking to address the need for medical care in resource‐limited environments, some have advocated for portable equipment in the hands of health‐care providers. We hypothesized that medical students are able to effectively teach point‐of‐care ultrasound (POCUS) to physicians, nurses, and midwives in rural Indonesia. Methods We conducted a prospective, observational study using health‐care practitioners from a clinic and accredited school for nursing and midwifery in Mojokerto, East Java, Indonesia. Enrolled practitioners took part in a 4‐week POCUS course followed by postinstructional testing. Results A total of 55 health‐care practitioners completed the course. This included 19 physicians, 13 nurses, and 19 midwives. Of the 55 clinicians, 43 (72%) passed the course and 12 (28%) failed. Conclusions Physicians, nurses, and midwives in rural Indonesia showed significant acquisition of ultrasound (US) knowledge and skills following a 4‐week US course. Following training, all three groups displayed skills in practical US use during a postcourse practical examination. This is one of the first studies to assess the efficacy of medical students teaching POCUS to midwives and nurses.
Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring based on non-genomic adaptation was validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.
Background While the benefit of admission to trauma centers compared to non-trauma centers is well-documented and differences in outcomes between Level-I and Level-II trauma centers are well-studied, data on the differences in outcomes between Level-II trauma centers (L2TCs) and Level-III trauma centers (L3TCs) are scarce. Objectives We sought to compare mortality risk between patients admitted to L2TCs and L3TCs, hypothesizing no difference in mortality risk for patients treated at L3TCs compared to L2TCs. Methods A retrospective analysis of the 2016 Trauma Quality Improvement Program (TQIP) database was performed. Patients aged 18+ years were divided into 2 groups, those treated at American College of Surgeons (ACS) verified L2TCs and L3TCs. Results From 74,486 patients included in this study, 74,187 (99.6%) were treated at L2TCs and 299 (.4%) at L3TCs. Both groups had similar median injury severity scores (ISSs) (10 vs 10, P < .001); however, L2TCs had a higher mean ISS (14.6 vs 11.9). There was a higher mortality rate for L2TC patients (6.0% vs 1.7%, P = .002) but no difference in associated risk of mortality between the 2 groups (OR .46, CI .14-1.50, P = .199) after adjusting predictors of mortality. L2TC patients had a longer median length of stay (5.0 vs 3.5 days, P < .001). There was no difference in other outcomes including myocardial infarction (MI) and cerebrovascular accident (CVA) ( P > .05). Discussion Patients treated at L2TCs had a longer LOS compared to L3TCs. However, after controlling for covariates, there was no difference in associated mortality risk between L2TC and L3TC patients.
Several machine learning and deep learning frameworks have been proposed to solve remaining useful life estimation and failure prediction problems in recent years. Having access to the remaining useful estimation or the likelihood of failure in the near future help operators to assess the operating conditions and, therefore, making better repair and maintenance decisions. However, many operators believe remaining useful life estimation and failure prediction solutions are incomplete answers to the maintenance challenge. They would argue that knowing the likelihood of failure in a given time interval or having access to an estimation of the remaining useful life are not enough to make maintenance decisions which minimize the cost while keeping them safe. In this paper, we present a maintenance framework based on off-line deep reinforcement learning which instead of providing information such as likelihood of failure, suggests actions such as “continue the operation” or “visit a repair shop” to the operators in order to maximize the overall profit. Using off-line reinforcement learning makes it possible to learn the optimum maintenance policy from historical data without relying on expensive simulators. We demonstrate the application of our solution in a case study using NASA C-MAPSS dataset.
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