A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

BACKGROUND: The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection. METHODS: We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors. FINDINGS: We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor. CONCLUSIONS: Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors. FUNDING: Funded by Fate Therapeutics and NIH (R01CA238039).

Thumb reconstruction after radical tumor resection using free osteocutaneous lateral arm flap with secondary humerus fracture-a case report.

INTRODUCTION: Malignant diseases with infiltration of bony structures in the area of the phalanges or metacarpals require either amputation or complex reconstruction. The decision for reconstruction means to restore length, mobility, sensibility, stability as well as aesthetics. METHODS: We present a case of complex first ray reconstruction of the left hand using a free osteocutaneous lateral arm flap from the ipsilateral side. The reconstruction was performed after radical resection of an exulcerated squamous cell carcinoma, including the first metacarpal bone, trapezium, partial trapezoid and distal scaphoid as well as partial resection of the extensor pollicis longus, extensor pollicis brevis, abductor pollicis longus and flexor carpi radialis tendons. The osteosynthetic restoration was achieved distally by a double wire cerclage and a proximally by temporary K-wire suspension. Moreover, to reconstruct the extensor pollicis longus tendon the ipsilateral palmaris longus tendon was harvested and used. Postoperatively, a secondary humerus fracture occurred, which was initially attended by plate osteosynthesis. The fracture showed delayed healing, which was treated by re-plating and autologous cancellous bone. RESULTS: 12 months postoperatively, the patient showed an excellent outcome with length preservation and good range of motion, sensibility, stability and aesthetic of the thumb. Furthermore, the quarterly tumor aftercare showed no evidence of recurrence. CONCLUSION: This case report showed that the free osteocutaneous lateral arm flap is a reliable solution for the reconstruction of the first ray with a great functional and aesthetic outcome. To prevent a secondary humerus fracture, a preventive plate osteosynthesis simultaneous with the osteocutaneous flap elevation should be considered.

Gastrointestinal Microbiome Disruption and Antibiotic-Associated Diarrhea in Children Receiving Antibiotic Therapy for Community-Acquired Pneumonia.

Antibiotic-associated diarrhea (AAD) is a common side effect of antibiotics. We examined the gastrointestinal microbiota in children treated with ß-lactams for community-acquired pneumonia. Data were from 66 children (n = 198 samples), aged 6-71 months, enrolled in the SCOUT-CAP trial (NCT02891915). AAD was defined as ≥1 day of diarrhea. Stool samples were collected on study days 1, 6-10, and 19-25. Samples were analyzed using 16S ribosomal RNA gene sequencing to identify associations between patient characteristics, microbiota characteristics, and AAD (yes/no). Nineteen (29%) children developed AAD. Microbiota compositional profiles differed between AAD groups (permutational multivariate analysis of variance, P < .03) and across visits (P < .001). Children with higher baseline relative abundances of 2 Bacteroides species were less likely to experience AAD. Higher baseline abundance of Lachnospiraceae and amino acid biosynthesis pathways were associated with AAD. Children in the AAD group experienced prolonged dysbiosis (P < .05). Specific gastrointestinal microbiota profiles are associated with AAD in children.

Camera-based assessment of cutaneous perfusion strength in a clinical setting.

Objective. After skin flap transplants, perfusion strength monitoring is essential for the early detection of tissue perfusion disorders and thus to ensure the survival of skin flaps. Camera-based photoplethysmography (cbPPG) is a non-contact measurement method, using video cameras and ambient light, which provides spatially resolved information about tissue perfusion. It has not been researched yet whether the measurement depth of cbPPG, which is limited by the penetration depth of ambient light, is sufficient to reach pulsatile vessels and thus to measure the perfusion strength in regions that are relevant for skin flap transplants.Approach. We applied constant negative pressure (compared to ambient pressure) to the anterior thighs of 40 healthy subjects. Seven measurements (two before and five up to 90 min after the intervention) were acquired using an RGB video camera and photospectrometry simultaneously. We investigated the performance of different algorithmic approaches for perfusion strength assessment, including the signal-to-noise ratio (SNR), its logarithmic components logS and logN, amplitude maps, and the amplitude height of alternating and direct signal components.Main results. We found strong correlations of up tor= 0.694 (p< 0.001) between photospectrometric measurements and all cbPPG parameters except SNR when using the green color channel. The transfer of cbPPG signals to POS, CHROM, and O3C did not lead to systematic improvements. However, for direct signal components, the transformation to O3C led to correlations of up tor= 0.744 (p< 0.001) with photospectrometric measurements.Significance. Our results indicate that a camera-based perfusion strength assessment in tissue with deep-seated pulsatile vessels is possible.

Topical negative pressure wound therapy enhances the local tissue perfusion - A pilot study.

BACKGROUND: Topical negative pressure wound therapy (TNPWT) is a regularly used method in modern wound treatment with a growing and diverse potential for clinical use. So far positive effects on microcirculation have been observed and examined, although precise statements on the underlying mechanism appear unsatisfying. OBJECTIVE: The aim of our study was to extend the understanding of the effect of TNPWT on tissue perfusion and determine the time frame and the extent to which the tissue perfusion changes due to TNPWT. MATERIAL AND METHODS: TNPWT was applied to the anterior thighs of 40 healthy individuals for 30 min, respectively. Before and up to 90 min after the application, measurements of the amount of regional haemoglobin (rHb), capillary venous oxygen saturation (sO2), blood flow (flow) and velocity were conducted with spectrophotometry (combining white light spectrometry and laser Doppler spectroscopy) within two different depths/skin layers. A superficial measuring probe for depths up to 3 mm and a deep measuring probe for up to 7 mm were used. RESULTS: All parameters show significant changes after the intervention compared to baseline measurements. The greater effect was seen superficially. The superficially measured rHb, sO2 and flow showed a significant increase and stayed above the baseline at the end of the protocol. Whereas deeply measured, the rHb initially showed a decrease. The flow and sO2 showed a significant increase up to 60 min after the intervention. CONCLUSION: The application of TNPWT on healthy tissue shows an increase in capillary-venous oxygen saturation and haemoglobin concentration of at least 90 min after intervention. A possible use in clinical practice for preconditioning to enhance wound healing for high-risk patients to develop wound healing disorder, requires further studies to investigate the actual duration of the effect.

The nature of cell division forces in epithelial monolayers.

Epithelial cells undergo striking morphological changes during division to ensure proper segregation of genetic and cytoplasmic materials. These morphological changes occur despite dividing cells being mechanically restricted by neighboring cells, indicating the need for extracellular force generation. Beyond driving cell division itself, forces associated with division have been implicated in tissue-scale processes, including development, tissue growth, migration, and epidermal stratification. While forces generated by mitotic rounding are well understood, forces generated after rounding remain unknown. Here, we identify two distinct stages of division force generation that follow rounding: (1) Protrusive forces along the division axis that drive division elongation, and (2) outward forces that facilitate postdivision spreading. Cytokinetic ring contraction of the dividing cell, but not activity of neighboring cells, generates extracellular forces that propel division elongation and contribute to chromosome segregation. Forces from division elongation are observed in epithelia across many model organisms. Thus, division elongation forces represent a universal mechanism that powers cell division in confining epithelia.

Bellymount enables longitudinal, intravital imaging of abdominal organs and the gut microbiota in adult Drosophila.

Cell- and tissue-level processes often occur across days or weeks, but few imaging methods can capture such long timescales. Here, we describe Bellymount, a simple, noninvasive method for longitudinal imaging of the Drosophila abdomen at subcellular resolution. Bellymounted animals remain live and intact, so the same individual can be imaged serially to yield vivid time series of multiday processes. This feature opens the door to longitudinal studies of Drosophila internal organs in their native context. Exploiting Bellymount's capabilities, we track intestinal stem cell lineages and gut microbial colonization in single animals, revealing spatiotemporal dynamics undetectable by previously available methods.

Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of division, differentiation and loss.

Organ renewal is governed by the dynamics of cell division, differentiation and loss. To study these dynamics in real time, we present a platform for extended live imaging of the adult Drosophila midgut, a premier genetic model for stem-cell-based organs. A window cut into a living animal allows the midgut to be imaged while intact and physiologically functioning. This approach prolongs imaging sessions to 12-16 hr and yields movies that document cell and tissue dynamics at vivid spatiotemporal resolution. By applying a pipeline for movie processing and analysis, we uncover new and intriguing cell behaviors: that mitotic stem cells dynamically re-orient, that daughter cells use slow kinetics of Notch activation to reach a fate-specifying threshold, and that enterocytes extrude via ratcheted constriction of a junctional ring. By enabling real-time study of midgut phenomena that were previously inaccessible, our platform opens a new realm for dynamic understanding of adult organ renewal.

Notes from the Field: Measles Outbreak of Unknown Source - Shelby County, Tennessee, April-May 2016.

On April 15, 2016, local public health officials in Shelby County, Tennessee, were notified of a positive measles immunoglobulin M (IgM) test for a male aged 18 months (patient A). On April 18, 2016, a second positive measles IgM test was reported for a man aged 50 years (patient B). Both patients had rash onset on April 9, 2016. The Shelby County Health Department initiated an investigation, and confirmatory testing for measles virus on oropharyngeal swabs by polymerase chain reaction (PCR) at CDC was positive for both patients. On April 21, 2016, public health officials were notified of a third suspected measles case in a female aged 7 months (patient C) who had developed a rash on April 14; PCR testing was positive. Genotyping conducted at CDC identified genotype B3 measles virus in all three cases. Genotype B3 is known to be circulating globally and has previously been associated with imported cases in the United States (1).

African American Women: Surviving Breast Cancer Mortality against the Highest Odds.

Among the country's 25 largest cities, the breast cancer mortality disparity is highest in Memphis, Tennessee, where African American women are twice as likely to die from breast cancer as White women. This qualitative study of African-American breast cancer survivors explores experiences during and post treatment that contributed to their beating the high odds of mortality. Using a semi-structured interview guide, a focus group session was held in 2012 with 10 breast cancer survivors. Thematic analysis and a deductive a priori template of codes were used to analyze the data. Five main themes were identified: family history, breast/body awareness and preparedness to manage a breast cancer event, diagnosis experience and reaction to the diagnosis, family reactions, and impact on life. Prayer and family support were central to coping, and survivors voiced a cultural acceptance of racial disparities in health outcomes. They reported lack of provider sensitivity regarding pain, financial difficulties, negative responses from family/friends, and resiliency strategies for coping with physical and mental limitations. Our research suggested that a patient-centered approach of demystifying breast cancer (both in patient-provider communication and in community settings) would impact how women cope with breast cancer and respond to information about its diagnosis.

The association of tobacco marketing with median income and racial/ethnic characteristics of neighbourhoods in Omaha, Nebraska.

OBJECTIVE: To examine the association of point-of-sale tobacco marketing with median income and racial/ethnic composition at the neighbourhood level in Omaha Metropolitan Area, Nebraska. METHODS: Fieldworkers collected comprehensive tobacco marketing data from all of the stores that were licensed to sell tobacco in 84 randomly selected neighbourhoods in the Omaha Metropolitan Area, Nebraska. RESULTS: An increase of $10,000 in median household income was associated with a decrease of 14.3% in the number of tobacco marketing items per square mile in a neighbourhood (p=0.021). There was very little evidence that the percentages of African-American and Hispanic populations in the neighbourhoods were related to tobacco marketing. CONCLUSION: Banning tobacco marketing, as recommended by the Framework Convention on Tobacco Control, is likely to reduce tobacco use disparities.

Kinesin-dependent transport results in polarized migration of the nucleus in oocytes and inward movement of yolk granules in meiotic embryos.

During female meiosis, meiotic spindles are positioned at the oocyte cortex to allow expulsion of chromosomes into polar bodies. In C. elegans, kinesin-dependent translocation of the entire spindle to the cortex precedes dynein-dependent rotation of one spindle pole toward the cortex. To elucidate the role of kinesin-1 in spindle translocation, we examined the localization of kinesin subunits in meiotic embryos. Surprisingly, kinesin-1 was not associated with the spindle and instead was restricted to the cytoplasm in the middle of the embryo. Yolk granules moved on linear tracks, in a kinesin-dependent manner, away from the cortex, resulting in their concentration in the middle of the embryo where the kinesin was concentrated. These results suggest that cytoplasmic microtubules might be arranged with plus ends extending inward, away from the cortex. This microtubule arrangement would not be consistent with direct transport of the meiotic spindle toward the cortex by kinesin-1. In maturing oocytes, the nucleus underwent kinesin-dependent migration to the future site of spindle attachment at the anterior cortex. Thus the spindle translocation defect observed in kinesin-1 mutants may be a result of failed nuclear migration, which places the spindle too far from the cortex for the spindle translocation mechanism to function.

Health risk characteristics of Black female informal caregivers on welfare.

This exploratory study examines differences in health risk characteristics and perceived health by caregiver status in two groups of Black women, 37 informal caregivers and 20 noncaregivers, transitioning from welfare to work. Health risk characteristics were assessed with the Center for Epidemiologic Studies Depression Scale and Healthier People Network Health Risk Appraisal-Version 6. Body mass index (BMI) calculations were based on the standard Centers for Disease Control formula. Perceived health status was assessed using a single-item Cantril ladder. Results show no statistically significant between-group differences in perceived health status, depressive symptoms, frequency of lifestyle behaviors, or BMI. Clinically significant proportions of participants in both groups rated their health as poor or fair; reported mild to severe depressive symptoms; smoked cigarettes; did not perform monthly self-breast exams; were physically inactive, overweight, or obese; and consumed high-fat diets. Black women receiving welfare show increased risk for premature chronic health problems, which warrants development of effective community-based risk-reduction programs.

Depressive symptoms, cardiovascular risk, and diabetes self-care strategies in African American women with type 2 diabetes.

This descriptive study examined depressive symptoms, cardiovascular risk, and diabetes self-care strategies in African American women (N = 45) with type 2 diabetes (T2D). All completed a questionnaire packet during structured interviews. Significant associations were found between two individual depressive symptoms and mean cardiovascular disease (CVD) risk scores, which suggest that in African American women with T2D, depressive symptoms may be correlated with a specific CVD profile and/or are unrecognized and/or unexpressed. Further analysis is warranted to determine the extent of this relationship in African American women with T2D.

Is your patient ready for transport? Developing an ICU patient transport decision scorecard.

Transport of patients from the intensive care unit (ICU) to another area of the hospital can pose serious risks if the patient has not been assessed prior to transport. Recently, the Department of Critical Care Medicine, Calgary Health Region, experienced two adverse events during transport. A subgroup of the Department's Patient Safety and Adverse Events team developed an ICU patient transport decision scorecard. This tool was tested through Plan-Do-Study-Act cycles and further revised using human factors principles. Staff, especially novice nurses, found the tool extremely useful in determining patient preparedness for transport.

Domestic violence as witnessed by New Zealand children.

BACKGROUND: This study reports on domestic violence in New Zealand families witnessed by members of the Dunedin Multidisciplinary Health and Development Study. METHOD: Questions on the witnessing of father to mother and mother to father physical violence and threats of harm up to the age of 18 were included in a retrospective family violence interview carried out when the cohort was interviewed at age 26. Study members who reported violence between parents were asked about the nature, context, and consequences of this violence. RESULTS: One-quarter (24%) of the sample reported violence or threats of violence directed from one parent to the other. Nine percent reported infrequent assaults while one in 10 reported more than five acts of physical violence. In violent families, 55% reported violence by fathers only, 28% by both partners, and 16% by mothers only. Almost 90% of the exposed group witnessed violence between natural parents, and 80% were exposed to violence before the age of 11. The gender of the study member or parent did not predict how upset study members were, but frequency of violence did. Witnesses were more likely than non-witnesses to have diagnoses of anxiety and depression at age 21. Socioeconomic status and age of parents were related to violence patterns, but not the mother's education or employment status. CONCLUSION: This study suggests that a quarter of young adults have been exposed to acts or threats of violence carried out by one parent toward another parent, and the majority found such witnessing to be a very upsetting experience. Public education programmes should emphasise that all violence carries risk of harm to all family members.

On the receiving end: young adults describe their parents' use of physical punishment and other disciplinary measures during childhood.

AIM: To investigate the prevalence, nature, and context of physical punishment and other forms of parental discipline, as reported by study members (SMs) of the Dunedin Multidisciplinary Health and Development Study. METHODS: 962 26-year-old adults (born in Dunedin, New Zealand) were interviewed about their experiences of discipline in childhood. Study members were asked about the usual forms of punishment received in primary and secondary school years, as well as the worst punishment they ever received. Details regarding the study members' reactions to different punishments were collected. Variables related to the person administering the punishment were also investigated. RESULTS: Of the study members providing data, 80% reported receiving physical punishment at some time during childhood: 29% identifying smacking; 45% reporting being hit with an object; and 6% reporting extreme physical punishment as the most severe form. Physical punishment on a regular basis was reported by 71% of study members. Results varied by age with more study members reporting physical punishment in primary school years. However, the number of study members experiencing physical punishment in adolescence was still high, at 47%. Significant gender differences were found in reported punishment, with more girls smacked, and more boys hit with an object in primary school years. Punisher-related reports showed that mothers were significantly more likely to employ non-physical forms of punishment whereas fathers were significantly more likely to use extreme physical punishment. CONCLUSION: For many New Zealanders, experiences of physical punishment during childhood are very much the norm. These findings have implications for the young adults studied as they now enter the parenting years and for efforts aimed at prevention and early intervention for at-risk groups.

SCER and SCAN: two novel high-prevalence antigens in the Scianna blood group system.

BACKGROUND: More than 20 years ago, two probands were described whose red blood cells (RBCs) typed Sc:1,-2,3. Their serum samples contained alloantibodies reactive with all RBCs tested except those of the Sc:-1,-2,-3 phenotype. Cloning of the Scianna gene allowed us to determine the molecular bases of these samples. STUDY DESIGN AND METHODS: In a collaborative effort, the two probands' samples and also two Sc:-1,-2,-3 samples were obtained from frozen storage. All 11 SC (ERMAP) exons and their flanking regions were sequenced. RESULTS: The two probands with antibodies to Scianna-related antigens were homozygous, respectively, for an ERMAP(R81Q) allele caused by a G to A substitution at nucleotide 242 in the ERMAP gene and for an ERMAP(H26Y,G35S) allele, in which the G35S substitution was caused by a G to A substitution at nucleotide 103. Two patients with the Sc:-1,-2,-3 phenotype both carried ERMAP(R332X) alleles caused by a C to T substitution at nucleotide 994 that differed at one nucleotide position in the noncoding region of exon 11. In eight samples carrying orphan low-prevalence antigens, no ERMAP variants were detected that could be implicated in Scianna antigen expression. CONCLUSION: SCER and SCAN expanded the Scianna blood group system to seven antigens, have been assigned the ISBT numbers 013.006 (Sc6) and 013.007 (Sc7), and were associated with ERMAP(R81Q) and ERMAP(G35S) proteins, respectively. ERMAP(R332X) is a second molecular basis for the Sc(null) phenotype. The eight low-prevalence antigens By, To(a), Pt(a), Re(a), Je(a), Li(a), SARA, and Sk(a) do not belong to the Scianna blood group system.