Origins of cancer: ain't it just mature cells misbehaving?

A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.

Surprising multifunctionality of a Tritonia swim CPG neuron: C2 drives the early phase of post-swim crawling despite being silent during the behavior.

In response to a suitably aversive skin stimulus, the marine mollusk Tritonia diomedea launches an escape swim followed by several minutes of high-speed crawling. The two escape behaviors are highly dissimilar: whereas the swim is a muscular behavior involving alternating ventral and dorsal whole-body flexions, the crawl is a non-rhythmic gliding behavior mediated by the beating of foot cilia. The serotonergic dorsal swim interneurons (DSIs) are members of the swim CPG and also strongly drive crawling. While the swim network is very well understood, the Tritonia crawling network to date comprises only three neurons: the DSIs, and pedal neurons 5 and 21 (Pd5 and Pd21). Since Tritonia's swim network has been suggested to have arisen from a pre-existing crawling network, we examined the possible role that another swim CPG neuron, C2, may play in crawling. Due to its complete silence in the post-swim crawling period, C2 had not previously been considered to play a role in driving crawling. However, semi-intact preparation experiments demonstrated that a brief C2 spike train surprisingly and strongly drives the foot cilia for ~30 s, something which cannot be explained by its synaptic connections to Pd5 and Pd21. Voltage-sensitive dye (VSD) imaging in the pedal ganglion identified many candidate crawling motor neurons that fire at an elevated rate following the swim, and also revealed several pedal neurons that are strongly excited by C2. It is intriguing that unlike the DSIs, which fire tonically after the swim to drive crawling, C2 does so despite its post-swim silence.

Division of labor for defensive retaliation and preemption by the peripheral and central nervous systems in the nudibranch Berghia.

Relatively little is known about how peripheral nervous systems (PNSs) contribute to the patterning of behavior in which their role transcends the simple execution of central motor commands or mediation of reflexes. We sought to draw inferences to this end in the aeolid nudibranch Berghia stephanieae, which generates a rapid, dramatic defense behavior, "bristling." This behavior involves the coordinated movement of cerata, dozens of venomous appendages emerging from the animal's mantle. Our investigations revealed that bristling constitutes a stereotyped but non-reflexive two-stage behavior: an initial adduction of proximate cerata to sting the offending stimulus (stage 1) followed by a coordinated radial extension of remaining cerata to create a pincushion-like defensive screen around the animal (stage 2). In decerebrated specimens, stage 1 bristling was preserved, while stage 2 bristling was replaced by slower, uncoordinated ceratal movements. We conclude from these observations that, first, the animal's PNS and central nervous system (CNS) mediate stages 1 and 2 of bristling, respectively; second, the behavior propagates through the body utilizing both peripheral- and central-origin nerve networks that support different signaling kinetics; and third, the former network inhibits the latter in the body region being stimulated. These findings extend our understanding of the PNS' computational capacity and provide insight into a neuroethological scheme in which the CNS and PNS both independently and interactively pattern different aspects of non-reflexive behavior.

Exploring the Diagnostic Dilemma of Indeterminate Pulmonary Nodules in Patients with Primary Sarcoma of Bone.

Introduction: Bone sarcomas are known to have a predilection for pulmonary metastasis. Surveillance protocols are thus focused on periodic chest imaging, typically with CT scan. Pulmonary nodules can be easily identified with this modality, but smaller nodules are not readily biopsied and may not represent metastatic disease. These are called indeterminate. The natural history of indeterminate nodules in a bone sarcoma population and factors associated with progression to true metastatic disease are not clearly defined. Methods: All bone sarcoma patients treated at a single institution from 2010 to 2020 were eligible for inclusion. We treated 327 patients over this period; 119 were excluded for age less than 16 years, 31 were excluded for evident metastatic disease at presentation, and 60 were excluded for incomplete clinical follow-up or CT chest imaging either at staging or in surveillance. We assessed chest CT images for presence of pulmonary nodules and selected variables both at the staging and on surveillance images. Nodules were considered metastatic if proven histologically with a biopsy or by clinical interpretation by the multidisciplinary sarcoma team. Clinical and imaging factors were assessed for the association of indeterminate nodule progression to true metastatic disease. Results: Seventy three of the 117 patients had indeterminate nodules on their staging CT scan; 41.1% of those patients progressed to metastatic disease compared to 43.2% of the patients that did not have indeterminate nodules on staging CT. Fifty eight of the 117 patients developed indeterminate nodules on surveillance chest CT, and 55.2% of those patients progressed to metastatic disease. There were no clinical or imaging factors that predicted the development of metastatic disease in the group that had indeterminate nodules at presentation; however, the number and size of nodules did correlate with progression to metastasis in those that developed indeterminate nodules on surveillance. Conclusion: Indeterminate pulmonary nodules are common on staging CT scans in patients with a bone sarcoma. The presence or absence of these indeterminate nodules was not predictive of progression to true metastatic disease in this cohort. However, the development of indeterminate nodules on surveillance imaging was associated with progression to metastatic disease with the size and number of nodules being important factors.

A new role for IFRD1 in regulation of ER stress in bladder epithelial homeostasis.

A healthy bladder requires the homeostatic maintenance of and rapid regeneration of urothelium upon stress/injury/infection. Several factors have been identified to play important roles in urothelial development, injury and disease response, however, little is known about urothelial regulation at homeostasis. Here, we identify a new role for IFRD1, a stress-induced gene that has recently been demonstrated to play a critical role in adult tissue proliferation and regeneration, in maintenance of urothelial function/ homeostasis in a mouse model. We show that the mouse bladder expresses IFRD1 at homeostasis and its loss alters the global transcriptome of the bladder with significant accumulation of cellular organelles including multivesicular bodies with undigested cargo, lysosomes and mitochondria. We demonstrate that IFRD1 interacts with several mRNA-translation-regulating factors in human urothelial cells and that the urothelium of Ifrd1-/- mice reveal decreased global translation and enhanced endoplasmic reticulum (ER) stress response. Ifrd1-/- bladders have activation of the unfolded protein response (UPR) pathway, specifically the PERK arm, with a concomitant increase in oxidative stress and spontaneous exfoliation of urothelial cells. Further, we show that such increase in cell shedding is associated with a compensatory proliferation of the basal cells but impaired regeneration of superficial cells. Finally, we show that upon loss of IFRD1, mice display aberrant voiding behavior. Thus, we propose that IFRD1 is at the center of many crucial cellular pathways that work together to maintain urothelial homeostasis, highlighting its importance as a target for diagnosis and/or therapy in bladder conditions.

Genetically engineered mouse model of pleomorphic liposarcoma: Immunophenotyping and histologic characterization.

INTRODUCTION: Pleomorphic liposarcoma is a rare and aggressive subset of soft-tissue sarcomas with a high mortality burden. Local treatment largely consists of radiation therapy and wide surgical resection, but options for systemic therapy in the setting of metastatic disease are limited and largely ineffective, prompting exploration of novel therapeutic strategies and experimental models. As with other cancers, sarcoma cell lines and patient-derived xenograft models have been developed and used to characterize these tumors and identify therapeutic targets, but these models have inherent limitations. The establishment of genetically engineered mouse models represents a more realistic framework for reproducing clinically relevant conditions for studying pleomorphic liposarcoma. METHODS: Trp53fl/fl/Rb1fl/fl/Ptenfl/fl (RPP) mice were used to reliably generate an immunocompetent model of mouse pleomorphic liposarcoma through Cre-mediated conditional silencing of the Trp53, Rb1, and Pten tumor suppressor genes. Evaluation of tumor-infiltrating lymphocytes was assessed with immunostaining for CD4, CD8, and PD-L1, and flow cytometry with analysis of CD45, CD3, CD4, CD8, CD19, F4/80, CD11b, and NKp46 sub-populations. RESULTS: Mice reliably produced noticeable soft-tissue tumors in approximately 6 weeks with rapid tumor growth between 100 and 150 days of life, after which mice reached euthanasia criteria. Histologic features were consistent with pleomorphic liposarcoma, including widespread pleomorphic lipoblasts. Immunoprofiling and assessment of tumor-infiltrating lymphocytes was consistent with other soft-tissue sarcomas. CONCLUSION: Genetically engineered RPP mice reliably produced soft-tissue tumors consistent with pleomorphic liposarcoma, which immunological findings similar to other soft-tissue sarcomas. This model may demonstrate utility in testing treatments for this rare disease, including immunomodulatory therapies.

Patient Outcomes in Traumatic Subarachnoid Hemorrhage: A Retrospective Analysis.

INTRODUCTION: Patients with isolated traumatic subarachnoid hemorrhage (itSAH) are often transferred to a Level I or II trauma center for neurosurgical evaluation. Recent literature suggests that some patients, such as those with high Glasgow Coma Scale (GCS) scores, may be safely observed without neurosurgical consultation. The objective of this study was to investigate characteristics of patients with itSAH to determine the clinical utility of neurosurgical evaluation and repeat imaging. MATERIALS AND METHODS: A retrospective chart review of 350 patients aged ≥ 18 y with initial computed tomography head (CTH) showing itSAH and GCS scores of 13-15. Patient demographics, medical history, medications, length of stay, transfer status, injury type and severity, and CTH results were extracted for analysis. Bivariate analyses were conducted to determine whether any factors were associated with a worsening repeat CTH. RESULTS: Most patients were female (57.4%) with blunt injuries (99.1%). The median age was 73 y. Neurosurgery was consulted for 342 (97.7%) patients, with one (0.3%) requiring intervention. Of 311 (88.9%) repeat imaging, 16 (5.1%) showed worsening. Factors with statistically significant associations with worsening CTH included injury severity; neurological deficit; lengths of stay; and a history of congestive heart failure, cirrhosis, or substance use disorder. CONCLUSIONS: The findings suggest that patients with itSAH and high GCS scores may be able to be managed safely without neurosurgical oversight. The factors strongly associated with worsening CTH may be useful in identifying patients who need transfer for intensive care. Further research is needed to confirm these findings and develop appropriate management strategies for patients with itSAH.

A common modular design of nervous systems originating in soft-bodied invertebrates.

Nervous systems of vertebrates and invertebrates show a common modular theme in the flow of information for cost-benefit decisions. Sensory inputs are incentivized by integrating stimulus qualities with motivation and memory to affect appetitive state, a system of homeostatic drives, and labelled for directionality. Appetitive state determines action responses from a repertory of possibles and transmits the decision to a premotor system that frames the selected action in motor arousal and appropriate postural and locomotion commands. These commands are then sent to the primary motor pattern generators controlling the motorneurons, with feedback at each stage. In the vertebrates, these stages are mediated by forebrain pallial derivatives for incentive and directionality (olfactory bulb, cerebral cortex, pallial amygdala, etc.) interacting with hypothalamus (homeostasis, motivation, and reward) for action selection in the forebrain basal ganglia, the mid/hindbrain reticular formation as a premotor translator for posture, locomotion, and arousal state, and the spinal cord and cranial nuclei as primary motor pattern generators. Gastropods, like the predatory sea slug Pleurobranchaea californica, show a similar organization but with differences that suggest how complex brains evolved from an ancestral soft-bodied bilaterian along with segmentation, jointed skeletons, and complex exteroceptors. Their premotor feeding network combines functions of hypothalamus and basal ganglia for homeostasis, motivation, presumed reward, and action selection for stimulus approach or avoidance. In Pleurobranchaea, the premotor analogy to the vertebrate reticular formation is the bilateral "A-cluster" of cerebral ganglion neurons that controls posture, locomotion, and serotonergic motor arousal. The A-cluster transmits motor commands to the pedal ganglia analogs of the spinal cord, for primary patterned motor output. Apparent pallial precursors are not immediately evident in Pleurobranchaea's central nervous system, but a notable candidate is a subepithelial nerve net in the peripheral head region that integrates chemotactile stimuli for incentive and directionality. Evolutionary centralization of its computational functions may have led to the olfaction-derived pallial forebrain in the ancestor's vertebrate descendants and their analogs in arthropods and annelids.

Anti-SARS-CoV-2 monoclonal antibodies for the treatment of mild-to-moderate COVID-19 in multiple sclerosis: A retrospective cohort study.

BACKGROUND: The use and potential benefit of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in people living with multiple sclerosis (pwMS) remains poorly studied. The objective of this study is to describe the therapeutic use of anti-SARS-CoV-2 mAbs among pwMS. METHODS: This retrospective cohort study used electronic medical records data from the TriNetX Dataworks USA Network and included adult pwMS, diagnosed with COVID-19, who received anti-SARS-CoV-2 mAbs in the outpatient setting between November 2020 and April 2022. We analyzed COVID-19 severity at anti-SARS-CoV-2 mAb initiation and up to 30 days, stratified by before/after emergence of Omicron variant and by disease-modifying therapy (DMT). RESULTS: The study included 434 pwMS treated with anti-SARS-CoV-2 mAbs for mild-to-moderate COVID-19, including 270 patients before and 174 after Omicron emergence. Most pwMS were female (80.2%), mean age (SD) was 51.5 (12.5) years. Two-hundred-and-five patients were on DMTs, 51% of whom received anti-CD20s. One patient with moderate COVID-19 was hospitalized whilst receiving glatiramer acetate. No patients required intensive care and there were no deaths. COVID-19 outcomes were comparable following anti-SARS-CoV-2 mAb therapy in patients receiving different DMTs. CONCLUSION: Anti-SARS-CoV-2 mAb treatment for pwMS with mild-to-moderate COVID-19 may reduce the risk of COVID-19-related hospitalization and death.

Thermal necrosis in orthopedic bone tumors: experimental research.

Introduction: The extent of surgical resection in orthopedic oncology differs according to tumor biology. While malignant bone tumors are operatively managed with wide resection, benign bone tumors and metastatic carcinomas are often treated through intralesional excision and adjuvant modalities, including the elimination of residual neoplastic cells through thermal necrosis. This study investigates in vitro temperature thresholds for thermal necrosis in common orthopedic bone tumors. Methodology: Eleven cell lines, including metastatic carcinomas to bone (A549, A498, FU-UR-1, PC3, MDA-MB-231, TT, MCF7, and K1), giant cell tumor of bone, osteosarcoma (HG-63), and control non-neoplastic cells (HEK293) were cultured. Cells were exposed to thermal stress at varying times and temperatures and evaluated for survival and viability with crystal violet and MTT assays. Results: Both the MTT and crystal violet assay demonstrated statistically superior rates of viability and survival for A549 (lung carcinoma), FU-UR-1 (renal carcinoma), K1 (thyroid carcinoma), and MG-63 (osteosarcoma) cell lines compared to control (HEK293 cells) at 60°C. Additionally, the MTT assay demonstrated superior viability for PC3 (prostate carcinoma), MCF7 (breast carcinoma), and A498 (renal carcinoma) compared to control. All cell lines demonstrated significantly decreased survival and viability in temperatures more than 90°C. Conclusion: This study demonstrated in vitro thresholds for thermal necrosis for cell lines of common orthopedic tumors of bone. The A549 (lung carcinoma), K1 (thyroid carcinoma), and FU-UR-1 (renal carcinoma) cell lines demonstrated greater resistance to heat stress compared to non-neoplastic control cells. Temperatures in excess of 90°C are necessary to reliably reduce cell survival and viability to less than 10%.

Neural division of labor: the gastropod Berghia defends against attack using its PNS to retaliate and its CNS to erect a defensive screen.

Relatively little is known about how the peripheral nervous system (PNS) contributes to the patterning of behavior, in which its role transcends the simple execution of central motor commands or mediation of reflexes. We sought to draw inferences to this end in the aeolid nudibranch Berghia stephanieae, which generates a rapid, dramatic defense behavior, "bristling." This behavior involves the coordinated movement of cerata, dozens of venomous appendages emerging from the animal's mantle. Our investigations revealed that bristling constitutes a stereotyped but non-reflexive two-stage behavior: an initial adduction of proximate cerata to sting the offending stimulus (Stage 1), followed by a coordinated radial extension of remaining cerata to create a pincushion-like defensive screen around the animal (Stage 2). In decerebrated specimens, Stage 1 bristling was preserved, while Stage 2 bristling was replaced by slower, uncoordinated, and ultimately maladaptive ceratal movements. We conclude from these observations that 1) the PNS and central nervous system (CNS) mediate Stages 1 and 2 of bristling, respectively; 2) the behavior propagates through the body utilizing both peripheral- and central-origin nerve networks that support different signaling kinetics; and 3) the former network inhibits the latter in the body region being stimulated. These findings extend our understanding of the PNS's computational capacity and provide insight into a neuroethological scheme that may generalize across cephalized animals, in which the CNS and PNS both independently and interactively pattern different aspects of non-reflexive behavior.

Wilderness Rescue of a Hiker with Multiple Trapped Limbs by a Combined Wilderness and Urban Rescue Team Using High-Pressure Airbags.

We report on the case of a 28-y-old man with both legs and left arm trapped for nearly 6 h after falling and subsequently being trapped by a boulder during a hike in the wilderness. Extrication required equipment designed for urban environments and was operated by an unconventional team of rescue professionals. The patient experienced multiple right lower-extremity orthopedic injuries, acute kidney injury secondary to rhabdomyolysis, and bilateral segmental pulmonary emboli. In this article, we detail the extrication and review the treatment guidelines for crush injuries that focus on aggressive fluid resuscitation prior to and during extrication and medication administration only if hyperkalemia presents. Wilderness rescuers should plan for the use of unconventional rescue equipment in austere prolonged rescue scenarios.

A Road Map for Peer Review of Real-World Evidence Studies on Safety and Effectiveness of Treatments.

The growing acceptance of real-world evidence (RWE) in clinical and regulatory decision-making, coupled with increasing availability of health care data and advances in automated analytic approaches, has contributed to a marked expansion of RWE studies of diabetes and other diseases. However, a recent spate of high-profile retractions highlights the need for improvements in the conduct of RWE research as well as in the associated peer review and editorial processes. We review best pharmacoepidemiologic practices and common pitfalls regarding design, measurement, analysis, data validity, appropriateness, and generalizability of RWE studies. To enhance RWE study assessments, we propose that journal editors require 1) study authors to complete RECORD-PE, a reporting guideline for pharmacoepidemiological studies on routinely collected data, 2) availability of predetermined study protocols and analysis plans, 3) inclusion of pharmacoepidemiologists on the peer review team, and 4) provision of detail on data provenance, characterization, and custodianship to facilitate assessment of the data source. We recognize that none of these steps guarantees a high-quality research study. Collectively, however, they permit an informed assessment of whether the study was adequately designed and conducted and whether the data source used was fit for purpose.

Hospitalizations Are Increasing in Distal Upper Extremity Fractures.

Introduction Distal upper extremity (DUE) fractures are common and include bony fractures of the wrist, hand, and finger. DUE fractures can require hospital admission for clinical observation or surgical fixation. The trend of hospitalization rate for these injuries may more accurately predict future staffing needs, required resources, and expected revenue for orthopedic surgery hand services. The purpose of this study is to determine the trend of hospitalization percentage from 2009 to 2018 for patients presenting to the United States (US) emergency departments (EDs) with DUE fractures. Methods The National Electronic Injury Surveillance System (NEISS) was utilized to collect data from 138,700 patients with wrist, hand, or finger fractures presenting to the US EDs between 2009 and 2018. A total of 752 patients were excluded for ages less than two years old or no sex entry. The unadjusted and adjusted (age, sex, race, and fracture location) hospitalization rates across years were evaluated using binary logistic regression. Results From 2009 to 2018, 137,948 DUE fractures were reported, of which 4749 (3.4%) were hospitalized. Wrist fractures accounted for the highest amount (2953) and the highest proportion of hospitalized patients (62.2%). Higher hospitalization rates were seen among patients 40 years and older (p < 0.05). Together, the DUE fracture hospitalization rate increased significantly (p < 0.05) in 2016 (OR = 1.215, 95% CI = 1.070-1.380), 2017 (OR = 1.154, 95% CI = 1.016-1.311), and 2018 (OR = 1.154, 95% CI = 1.279-1.638) from 2009. The adjusted results showed hospitalization rate statistically increased (p < 0.05) in 2016 (OR = 1.184, 95% CI = 1.040-1.346) and 2018 (OR = 1.389, 95% CI = 1.225-1.575) compared to 2009. An inconsistent increase in hospitalization rate was seen across locations of fracture: wrist (2012, 2013, 2018), hand (2018), and finger (2016, 2018). Conclusions The hospitalization rate of patients with DUE fractures increased in 2016 and 2018 from 2009. These data may predict a need to increase future staffing and resources for orthopedic surgery hand services as hospitals resume pre-pandemic practices.

The association of varying treatment thresholds of mepolizumab on asthma exacerbations in adults.

Background: Asthma has a high healthcare burden globally, with up to 10% of the asthma population suffering from severe disease. Biologic agents are a newer class of asthma treatments for severe asthma, with good evidence for efficacy in clinical trials. Nevertheless, real-world studies of its impact on clinical outcomes are limited.Methods: This is an observational cohort study using administrative claims data. The study population consisted of patients aged ≥18 years who had a diagnosis of asthma and initiated mepolizumab after November 4, 2015 and had continuous medical and drug coverage in both the 365 days prior to and following mepolizumab initiation. In patients treated with mepolizumab, we described clinically significant asthma exacerbations by minimum continuous treatment thresholds following initiation of mepolizumab, medication switching patterns and chronic oral corticosteroid (≥28 days) use.Results: We identified 2,536 adults with asthma who initiated mepolizumab. There was an association toward reduction in severe asthma-related events over the first one year of exposure. We observed associations with reduced dispensings of oral corticosteroids over the first year after mepolizumab initiation. Very few patients switched to other biologics during the study period.Conclusions: Treatment with mepolizumab may be associated with fewer asthma-related events in the first year. Over the first one year after initiating mepolizumab, we found associations with decreased concomitant dispensings of oral corticosteroids and medium to high dose ICS/LABA. Additionally, most patients who initiated mepolizumab did not switch to other biologics.

Prevalence of Potential Drug-drug Interactions With Ritonavir-containing COVID-19 Therapy in the United States: An Analysis of the National Health and Nutrition Examination Survey.

PURPOSE: The evolving epidemiology and treatment landscape of COVID-19 necessitates research into potential drug-drug interactions (pDDIs) from the use of new treatments for COVID-19, particularly those that contain ritonavir, a potent inhibitor of the cytochrome P350 3A4 (CYP3A4) metabolic pathway. In this study, we assessed the prevalence of pDDIs between medications for chronic conditions metabolized through the CYP3A4 metabolic pathway and ritonavir-containing COVID-19 medications in the US general population. METHODS: This study combined National Health and Nutrition Examination Survey (NHANES) waves 2015 to 2016 and 2017 to March 2020 to observe pDDI prevalence between ritonavir-containing therapy and coadministered medications among US adults 18 years or older. CYP3A4-mediated medications were identified from affirmative medication questionnaire response and associated prescription examination by surveyors. CYP3A4-mediated medications with associated pDDIs with ritonavir and assessed pDDI severity (minor, major, moderate, and severe) were obtained from the University of Liverpool's COVID-19 online drug interaction checker, Lexicomp, and US Food and Drug Administration fact sheets. pDDI prevalence and severity were evaluated by demographic characteristics and COVID-19 risk factors. FINDINGS: A total of 15,685 adult participants were identified during the 2015 to 2020 NHANES waves. Survey participants used a mean (SD) of 2.7 (1.8) drugs with likelihood of a pDDI. The weighted prevalence of major to contraindicated pDDIs among the US population was 29.3%. Prevalence rates among those 60 years and older, with serious heart conditions, with moderate chronic kidney disease (CKD), with severe CKD, with diabetes, and with HIV were 60.2%, 80.7%, 73.9%, 69.5%, 63.4%, and 68.5%, respectively. Results remained largely unchanged after removal of statins from the list of drugs associated with ritonavir-based pDDIs. IMPLICATIONS: Approximately one-third of the US population would be at risk for a major or contraindicated pDDI should they receive a ritonavir-containing regimen, and this risk increases significantly among individuals 60 years or older and with comorbidities such as serious heart conditions, CKD, diabetes, and HIV. The state of polypharmacy in the US population and the quickly changing COVID-19 landscape indicate significant risk of pDDIs among those requiring treatment with ritonavir-containing COVID-19 medications. Practitioners should take polypharmacy, age, and comorbidity profile into account when prescribing COVID-19 therapies. Alternative treatment regimens should be considered, especially for those of older age and those with risk factors for progression to severe COVID-19.

RBM47 regulates intestinal injury and tumorigenesis by modifying proliferation, oxidative response, and inflammatory pathways.

RNA-binding protein 47 (RBM47) is required for embryonic endoderm development, but a role in adult intestine is unknown. We studied intestine-specific Rbm47-knockout mice (Rbm47-IKO) following intestinal injury and made crosses into ApcMin/+ mice to examine alterations in intestinal proliferation, response to injury, and tumorigenesis. We also interrogated human colorectal polyps and colon carcinoma tissue. Rbm47-IKO mice exhibited increased proliferation and abnormal villus morphology and cellularity, with corresponding changes in Rbm47-IKO organoids. Rbm47-IKO mice adapted to radiation injury and were protected against chemical-induced colitis, with Rbm47-IKO intestine showing upregulation of antioxidant and Wnt signaling pathways as well as stem cell and developmental genes. Furthermore, Rbm47-IKO mice were protected against colitis-associated cancer. By contrast, aged Rbm47-IKO mice developed spontaneous polyposis, and Rbm47-IKO ApcMin/+ mice manifested an increased intestinal polyp burden. RBM47 mRNA was decreased in human colorectal cancer versus paired normal tissue, along with alternative splicing of tight junction protein 1 mRNA. Public databases revealed stage-specific reduction in RBM47 expression in colorectal cancer associated independently with decreased overall survival. These findings implicate RBM47 as a cell-intrinsic modifier of intestinal growth, inflammatory, and tumorigenic pathways.

Coordination of Locomotion by Serotonergic Neurons in the Predatory Gastropod Pleurobranchaea californica.

Similar design characterizes neuronal networks for goal-directed motor control across the complex, segmented vertebrates, insects, and polychaete annelids with jointed appendages. Evidence is lacking for whether this design evolved independently in those lineages, evolved in parallel with segmentation and appendages, or could have been present in a soft-bodied common ancestor. We examined coordination of locomotion in an unsegmented, ciliolocomoting gastropod, the sea slug Pleurobranchaea californica, which may better resemble the urbilaterian ancestor. Previously, bilateral A-cluster neurons in cerebral ganglion lobes were found to compose a multifunctional premotor network controlling the escape swim and feeding suppression, and mediating action selection for approach or avoidance turns. Serotonergic As interneurons of this cluster were critical elements for swimming, turning, and behavioral arousal. Here, known functions were extended to show that the As2/3 cells of the As group drove crawling locomotion via descending signals to pedal ganglia effector networks for ciliolocomotion and were inhibited during fictive feeding and withdrawal. Crawling was suppressed in aversive turns, defensive withdrawal, and active feeding, but not during stimulus-approach turns or prebite proboscis extension. Ciliary beating was not inhibited during escape swimming. These results show how locomotion is adaptively coordinated in tracking, handling, and consuming resources, and in defense. Taken with previous results, they also show that the A-cluster network acts similarly to the vertebrate reticular formation with its serotonergic raphe nuclei in facilitating locomotion, postural movements, and motor arousal. Thus, the general scheme controlling locomotion and posture might well have preceded the evolution of segmented bodies and articulated appendages.SIGNIFICANCE STATEMENT Similar design in the neuronal networks for goal-directed motor control is seen across the complex, segmented vertebrates, insects, and polychaete annelids with jointed appendages. Whether that design evolved independently or in parallel with complexity in body and behavior has been unanswered. Here it is shown that a simple sea slug, with primitive ciliary locomotion and lacking segmentation and appendages, has similar modular design in network coordination as vertebrates for posture in directional turns and withdrawal, locomotion, and general arousal. This suggests that a general neuroanatomical framework for the control of locomotion and posture could have arisen early during the evolution of bilaterians.

3'-sulfated LewisA/C: An oncofetal epitope associated with metaplastic and oncogenic plasticity of the gastrointestinal foregut.

Metaplasia, dysplasia, and cancer arise from normal epithelia via a plastic cellular transformation, typically in the setting of chronic inflammation. Such transformations are the focus of numerous studies that strive to identify the changes in RNA/Protein expression that drive such plasticity along with the contributions from the mesenchyme and immune cells. However, despite being widely utilized clinically as biomarkers for such transitions, the role of glycosylation epitopes is understudied in this context. Here, we explore 3'-Sulfo-Lewis A/C, a clinically validated biomarker for high-risk metaplasia and cancer throughout the gastrointestinal foregut: esophagus, stomach, and pancreas. We discuss the clinical correlation of sulfomucin expression with metaplastic and oncogenic transformation, as well as its synthesis, intracellular and extracellular receptors and suggest potential roles for 3'-Sulfo-Lewis A/C in contributing to and maintaining these malignant cellular transformations.

Introduction of artificial light at night increases the abundance of predators, scavengers, and parasites in arthropod communities.

While recent studies explore the negative impacts of light pollution on arthropods, few studies investigated community-level responses to artificial light. Using an array of landscaping lights and pitfall traps, we track community composition over 15 consecutive days and nights, including a five-night pre-light period, a five-night during-light period, and a five-night post-light period. Our results highlight a trophic-level response to artificial nighttime lighting with shifts in the presence and abundance of predators, scavengers, parasites, and herbivores. We show that associated trophic shifts occurred immediately upon the introduction of artificial light at night and are limited to nocturnal communities. Lastly, trophic levels reverted to their pre-light state, suggesting many short-term changes in communities are likely the result of behavioral shifts. These trophic shifts may become common as light pollution increases, implicating artificial light as a cause of global arthropod community change and highlighting light pollution's role in global herbivorous arthropod decline.