MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.

Diversity and Evolution of Frog Visual Opsins: Spectral Tuning and Adaptation to Distinct Light Environments.

Visual systems adapt to different light environments through several avenues including optical changes to the eye and neurological changes in how light signals are processed and interpreted. Spectral sensitivity can evolve via changes to visual pigments housed in the retinal photoreceptors through gene duplication and loss, differential and coexpression, and sequence evolution. Frogs provide an excellent, yet understudied, system for visual evolution research due to their diversity of ecologies (including biphasic aquatic-terrestrial life cycles) that we hypothesize imposed different selective pressures leading to adaptive evolution of the visual system, notably the opsins that encode the protein component of the visual pigments responsible for the first step in visual perception. Here, we analyze the diversity and evolution of visual opsin genes from 93 new eye transcriptomes plus published data for a combined dataset spanning 122 frog species and 34 families. We find that most species express the four visual opsins previously identified in frogs but show evidence for gene loss in two lineages. Further, we present evidence of positive selection in three opsins and shifts in selective pressures associated with differences in habitat and life history, but not activity pattern. We identify substantial novel variation in the visual opsins and, using microspectrophotometry, find highly variable spectral sensitivities, expanding known ranges for all frog visual pigments. Mutations at spectral-tuning sites only partially account for this variation, suggesting that frogs have used tuning pathways that are unique among vertebrates. These results support the hypothesis of adaptive evolution in photoreceptor physiology across the frog tree of life in response to varying environmental and ecological factors and further our growing understanding of vertebrate visual evolution.

Fish and macroinvertebrate assemblages reveal extensive degradation of the world's rivers.

Rivers suffer from multiple stressors acting simultaneously on their biota, but the consequences are poorly quantified at the global scale. We evaluated the biological condition of rivers globally, including the largest proportion of countries from the Global South published to date. We gathered macroinvertebrate- and fish-based assessments from 72,275 and 37,676 sites, respectively, from 64 study regions across six continents and 45 nations. Because assessments were based on differing methods, different systems were consolidated into a 3-class system: Good, Impaired, or Severely Impaired, following common guidelines. The proportion of sites in each class by study area was calculated and each region was assigned a Köppen-Geiger climate type, Human Footprint score (addressing landscape alterations), Human Development Index (HDI) score (addressing social welfare), % rivers with good ambient water quality, % protected freshwater key biodiversity areas; and % of forest area net change rate. We found that 50% of macroinvertebrate sites and 42% of fish sites were in Good condition, whereas 21% and 29% were Severely Impaired, respectively. The poorest biological conditions occurred in Arid and Equatorial climates and the best conditions occurred in Snow climates. Severely Impaired conditions were associated (Pearson correlation coefficient) with higher HDI scores, poorer physico-chemical water quality, and lower proportions of protected freshwater areas. Good biological conditions were associated with good water quality and increased forested areas. It is essential to implement statutory bioassessment programs in Asian, African, and South American countries, and continue them in Oceania, Europe, and North America. There is a need to invest in assessments based on fish, as there is less information globally and fish were strong indicators of degradation. Our study highlights a need to increase the extent and number of protected river catchments, preserve and restore natural forested areas in the catchments, treat wastewater discharges, and improve river connectivity.

An alternative approach for the surgical correction of unilateral crossbite.

This case report aims to describe a modified surgically assisted rapid palatal expansion technique to treat an asymmetrical posterior crossbite with no mandibular shift without causing an interincisal diastema. A clinical patient with an asymmetrical crossbite, large tooth-size-arch length, and Bolton discrepancy is used to illustrate the modified technique. Instead of traditional osteotomies, in this technique, the osteotomy is done between the maxillary right canine and lateral incisor (connecting the piriform aperture to the alveolar process) along with a unilateral LeFort I osteotomy. The expansion forces are produced by the activation of a conventional hyrax appliance. The skeletal unilateral crossbite was corrected without major changes to the opposite side and without causing an anesthetic diastema between the maxillary central incisors. A mandibular incisor extraction produced the space needed to treat the tooth size-arch length and corrected the Bolton discrepancy. This allowed a successful treatment of the problems initially presented by the patient.

Loads of continuous mechanics for uprighting the second molar on the second molar and premolar.

INTRODUCTION: This paper aims to evaluate the effect of tube height on uprighting a mandibular second molar with a continuous arch, specifically the main effects on the molar tube and the side effects on the second premolar bracket. METHODS: Slot brackets (0.18-in) and tubes were passively bonded from the left second molar to the right second premolar of the patient's cast and fixed to an orthodontic force tester. A mesially tipped second molar along with its tube was positioned at 5 different heights in relation to the bracket slots of the remaining appliance: 2 mm below (group -2), 1 mm below (group -1), leveled (group 0), 1 mm above (group 1) and 2 mm above (group 2). Each group had 10 different 0.016 × 0.022-in superelastic nickel-titanium wires tied one at a time to the appliance to register the vertical forces (Fz) and tipping moments (Mx) produced at the molar tube and the premolar bracket, statistically. Analysis of variance was used to identify differences of load among the groups for wire response to the position of the tube in relation to the other brackets' slots. RESULTS: As the molar tube was positioned more occlusally, Fz and Mx decreased at the molar tube from 1.31 N to 0.75 N and 13.98 N.mm to 11.84 N.mm, respectively, whereas at the premolar bracket, Fz and Mx decreased from 1.52 N to 0.88 N and 8.77 N.mm to 1.05 N.mm, respectively. CONCLUSIONS: In all groups, the load system at the molar tube (the main effects) registered a distal tipping moment and an extrusive force, whereas at the premolar bracket, the load system (side effects) included a distal tipping moment and an intrusive force. As the tube moved occlusally, the extrusive force and the uprighting moment decreased, along with the side effects at the premolar bracket. Attempting to bond the molar tube more occlusally (within reasonable intraoral dimensions) when trying to upright a molar does not appear to be sufficient to keep a molar from extruding.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

Effect of essential oils against acaricide-susceptible and acaricide-resistant Rhipicephalus ticks.

The indiscriminate use of acaricides is a problem worldwide and has increased the selection of acaricide-resistant tick populations. The goal of this study was to evaluate the acaricide effects of two essential oils (from Schinus molle and Bulnesia sarmientoi) using the larval immersion test on three Rhipicephalus tick species. Rhipicephalus evertsi, Rhipicephalus appendiculatus and Rhipicephalus pulchelus ticks collected in Kenya, without history of acaricide exposure, were tested, as well as individuals from two populations of Rhipicephalus microplus (with or without history of acaricide exposure), for comparison. The sample most resistant to the treatments was a population of R. microplus with previous acaricide exposure, whereas the least tolerant sample was a strain of the same species that never had contact with acaricides (Porto Alegre strain). Interestingly, the field tick samples without previous acaricide exposure responded to essential oils with a mortality profile resembling that observed in the acaricide-resistant R. microplus field population, and not the susceptible Porto Alegre strain. The essential oil of B. sarmientoi and its two components tested (guaiol and bulnesol) caused the highest mortality rates in the tested species and are potential molecules for future studies on control methods against these species.

Managing Cancer Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal.

The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.

Continuous endometrial volumetric analysis for endometrial receptivity assessment on assisted reproductive technology cycles.

BACKGROUND: Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. In order to assess endometrial receptivity in Assisted Reproductive Technology (ART) cycles serial evaluation of endometrial volumetric analysis may have a predictive value on a positive outcome. METHODS: Serial 3D transvaginal ultrasound performed in women on ART cycle to evaluate embryo implantation predictors. Prospective case control study of 169 subjects were assessed. Endometrial pattern, thickness, volume and adjusted endometrial volume (ratio between endometrial volume and uterine volume) was performed to all subjects on a continuous process from baseline, during controlled ovarian stimulation, trigger day with human chorionic gonadotropin hormone (hCG) and at embryo transfer day. RESULTS: Demographics and ART procedures and scores, was similar between the two groups. Endometrial morphology also showed no difference between the two groups. Endometrial volume and adjusted endometrial volume was significantly higher in the positive group as soon as day 6 of ovarian controlled stimulation. CONCLUSIONS: Serial 3D endometrial volume and adjusted endometrial volumes provides a predicting clinical tool enhancing elective embryo transfers in fresh ART cycle. Thus providing a non-invasive continuous technique for endometrial receptivity assessment that reflects endometrial changes during ART procedures.

Expansion with transpalatal arch or continuous arch mechanics.

INTRODUCTION: This study aimed to compare the 3-dimensional force system produced by transpalatal arch (TPA) mechanics with that produced by a continuous arch (CA) on the expansion of maxillary first molars. METHODS: A patient's model with 2 molars in 4-mm crossbite had orthodontic appliances bonded to all teeth. The first and the second molars were connected to two 3-dimensional load cells to compare the forces in the transverse and anteroposterior planes (Fx and Fy) and the rotational moments (Mz) produced in both molars by the expanded TPA and by 0.016-in nickel-titanium CA. The data were evaluated using 6 independent t tests, and the net moment at the molar's center of resistance was also calculated. RESULTS: All forces and moments were different at both molars. At the first molar, CA produced Fx of 2.60 N, Fy of -0.08 N, Mz of -5.16 N·mm, and Net Mz of -5.68 N·mm, whereas the TPA produced Fx of 2.87 N, Fy of -0.60 N, Mz of -22.08 N·mm, and Net Mz of -25.09 N·mm. At the second molar, the TPA did not produce significant forces and moments, whereas the CA produced Fx of -1.00 N, Mz of 3.95 N·mm, Fy of -0.84 N, and Net Mz of -0.67 N·mm. CONCLUSIONS: Based on our findings in a clinical set up with the specific horseshoe TPA and archwire tested, with the TPA used only on the first molars and the CA used from one second molar to the other, the mechanics produced different expansion forces at the first molar. The TPA produced a larger rotational side effect on the first molar, whereas the CA produced side effects on the second molar.

Concomitant permanent maxillary canine agenesis and transposition treated with extractions and lingual brackets.

This case report describes the successful orthodontic treatment for a healthy woman with maxillary canine-premolar transposition associated with rare hypodontia of the contralateral canine. The treatment included extraction of the transposed maxillary right and deciduous maxillary left canines and 2 mandibular second premolars. The objectives of the treatment were to (1) correct the upper midline deviation and the occlusal plane cant, (2) move the maxillary first premolars into the canine position, (3) retract the mandibular incisors to improve the facial profile, and (4) reduce the labial protrusion. Orthodontic treatment was carried out with the lingual technique in the maxillary arch and esthetic ceramic brackets in the mandibular arch. The segmented mechanics were effective, fast, and consistently promoted the necessary movement without side effects. The smile line was improved, resulting in an ideal and esthetic gingival exposition, with the borders of the maxillary teeth following the lower lip smile curvature. The patient achieved ideal dentofacial esthetics, achieved better dental and functional occlusion, was pleased with her improved facial contour, and as a result, showed an improved self-image.

Long term follow-up of neoadjuvant chemotherapy for non-small cell lung cancer (NSCLC) investigating early positron emission tomography (PET) scan as a predictor of outcome.

BACKGROUND: Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. METHODS: In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. RESULTS: Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). CONCLUSIONS: This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. TRIAL REGISTRATION: NCT00227539 registered September 28th, 2005.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."

Low-level laser therapy (830 nm) on orthodontic pain: blinded randomized clinical trial.

The objective of this research was to compare the effect single low-level laser therapy (LLLT) irradiation on pain perception in patients having fixed appliance treatment in the clinic of orthodontics. Sixty-two patients were recruited to participate in this randomized, double-blinded, placebo-controlled study. The patients were assigned to four groups: group I-laser on the right side; group II-placebo on the right side; group III-laser on the left side; group IV-placebo on the left. The laser or placebo was applied before separation, 24 and 48 h after separation of their first permanent molars in the lower arch. Just after the separation, the average of the pain for the placebo group was 1.6, significantly greater than the average of 1.1 registered for the laser group (p = 0.013). After 24 h and before the new irradiation, the values registered among the different groups did not show any differences. In relation to the gender, only after the first irradiation in placebo group, the female had a level of pain (0.1) significantly higher (p = 0.04) compared to male, and after 48 h, the group where the laser was applied had a difference (p = 0.04) among the gender with a value of lower pain for men (0.6) than for women (1.6).The laser irradiation to minimize the pain was only effective when applied immediately after treatment and separation. In general way, there were no differences between the genders, except after the first placebo group irradiation in which the female had a significantly higher level of pain compared to male and after 48 h. The pain cycle observed in this study had its peak in 24 h, both for laser's and placebo's group.

Racial disparity in oncologic and quality-of-life outcomes in patients with locally advanced head and neck squamous cell carcinomas enrolled in a randomized phase 2 trial.

BACKGROUND: To better understand patient-reported quality of life (PRQOL) for patients with head and neck cancer, PRQOL scores were collected in a clinical trial. METHODS: Patients were randomized to arm A (70 Gy of radiation with cisplatin) or arm B (70 Gy of radiation with cisplatin plus erlotinib at 150 mg daily). PRQOL scores were measured on days -7 (arm B only), 0, 30, and 180 with the University of Washington Quality of Life Questionnaire. Associations with clinical factors and outcomes were explored with linear mixed, logistic, and Cox regression models. RESULTS: One hundred eighty-nine patients (97 in arm A and 92 in arm B) consented to PRQOL collection. Patients were balanced apart from more females in arm A (20 [21%] vs 8 [9%]; P = .02). There were 17 black patients (18%) in arm A and 12 (13%) in arm B (P = .39). There was no change in the mean scores in arm B from day -7 to day 0 (P = .36). Scores were lower in both arms at day 30 (P for both < .0001), with no difference by arm (P = .10). Scores on day 180 remained lower for arm A (-6.79; 95% confidence interval [CI], -12.6 to -1.0; P = .02). In arm B, this difference was not significant, and this suggested that the scores had returned to the baseline by day 180 (P = .73). After adjustments for potential confounders, black race was an independent predictor for inferior scores (-11.4; 95% CI, -16.84 to -5.94; P < .0001), complete response rates (odds ratio, 0.34; 95% CI, 0.12-0.91; P = .03), and overall survival (hazard ratio, 3.71; 95% CI, 1.63-8.47; P < .01). CONCLUSIONS: PRQOL scores predictably worsened during and improved after chemoradiation. Black patients had inferior PRQOL and overall survival. Cancer 2018;124:2841-2849. © 2018 American Cancer Society.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Second molar intrusion: Continuous arch or loop mechanics?

INTRODUCTION: Our aim was to compare the load systems produced by rectangular loops and continuous arch mechanics on intrusion of a maxillary second molar. METHODS: An orthodontic appliance was passively bonded from second molar to second molar on a patient's model fixed to an orthodontic force tester. The second molars were extruded by 3 mm, and 2 mechanics systems were compared: beta-titanium rectangular loops and super-elastic nickel-titanium continuous arch. Vertical (Fz) and mesial (Fy) forces, and tipping moments around the buccal axis (Mx) at the tubes were collected at every 0.5 mm of deactivation. Repeated measures analysis of variance was used to detect differences between mechanics. The net Mx was also estimated at the center of resistance of each molar. RESULTS: Significant differences were found between the mechanics at the tubes, except for the Mx in the first molar, and more importantly, at the centers of resistance of the molars: Fz forces were greater in the continuous arch than in the rectangular loops, which, on the other hand, produced lower Fy forces than the continuous arch. In the second molar, net Mx was low initially and changed with deactivation. In the continuous arch, net Mx decreased from -3.6 N.mm of mesial crown tipping to clinically insignificant levels after 2 mm of deactivation. In the first molar, net Mx was lower on the rectangular loop than on the continuous arch during the first 2 mm of deactivation and became similar in the last millimeter of deactivation. Additionally, the net Mx decreased with deactivation with both mechanics. CONCLUSIONS: Both mechanics can intrude the second molars. Although the rectangular loop produced less tipping in large deflections, the continuous arch was a better approach when less intrusion was required.

Continuous arch and rectangular loops for the correction of consistent and inconsistent load systems in extruded and tipped maxillary second molars.

INTRODUCTION: The aim of this research was to compare the load systems produced by rectangular loops and continuous arches for the correction of extruded second molars with a mesial inclination (inconsistent system) and a distal inclination (consistent system). METHODS: The maxillary first molar of an acrylic model of a patient, with passive brackets and tubes bonded, was connected to a 3-dimensional load cell of an orthodontic force tester, and the second molar was replaced by its respective tube bonded to a second load cell. The second molar tube was moved 2.5 mm occlusally and tipped 20° mesially and distally, creating an inconsistent force system and a consistent force system. For each situation, ten 0.017 × 0.025-in beta-titanium, 8 × 10-mm rectangular loops were compared with 10 0.014-in nickel-titanium continuous arches. The vertical forces-F(z)-and tipping moments-M(x)-were compared using 4 t tests, at 5%. RESULTS: In the inconsistent group, the rectangular loop produced a larger M(x) in both molars: 2.11 N.mm in the second molar compared with the -0.15 N.mm of the continuous arches. On the first molar, the rectangular loops produced -5.58 N.mm against -2.08 N.mm produced by the continuous arches. The F(z) values produced at the second molar with each system were similar, whereas on the first molar they were different; the rectangular loops produced 0.41N, and continuous arches produced 0.53N. In the consistent group, the rectangular loops produced smaller M(x) values at the second molar (-3.06 N.mm) than did the continuous arch (-4.25 N.mm) (P = 0.01), as well as a smaller F(z) value (-0.52 vs -0.92 N, respectively). At the first molar, the rectangular loops produced smaller M(x) values (-2.32 N.mm) than did the continuous arch (-4.18 N.mm), as well as a smaller F(z) value (0.59 vs 1.10 N). CONCLUSIONS: In the inconsistent group, only the rectangular loop produced a system of force that could correct the second molar. In the consistent system, both group mechanics produced a system of force compatible with the correction of the second molar, but the continuous wire produced larger moments. Both groups showed a tendency for mesial crown tipping of the first molar.

Trigger tools are as effective as non-targeted chart review for adverse drug event detection in intensive care units.

OBJECTIVE: This study aimed to compare the use of trigger tools and non-targeted chart review as methods for the detection of adverse drug events in an intensive care unit considering the health system of a developing country. METHODS: Patients were divided in groups that were submitted to different methods (trigger tool and non-targeted chart review) for adverse drug event detection. Medical records were retrospectively reviewed, and adverse drug events detected during the data collection were analyzed by a multidisciplinary team and classified according to their causality, predictability, severity and damage level. RESULTS: The search for adverse events performed by trigger tools and non-targeted chart review allowed the identification of similar numbers of events (61.09 and 64.04 ADE/1000 patient-days, respectively), types of event and related drugs. In both groups, the most frequently detected adverse events were related to metabolic, gastrointestinal, cardiovascular and hematological systems. These organic systems matched the drugs most associated with adverse event occurrence: anti-infectives, antithrombotics and insulins. Events identified by non-targeted chart review presented higher causality relationships and were considered less severe than those observed by trigger tool use (p < 0.05). CONCLUSION: The similar performance between these methods supports trigger tool applicability in the ICU routine, as this methodology requires less time to retrieve information from the medical records.

Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.