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Guttman-Yassky E, Diaz A, Pavel AB, Tan K, He H, Xu H, Cueto I, Krueger JG
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Response to 'Lack of efficacy of dupilumab in the treatment of keloid disorder' by MH Tirgan and J Uitto (opens in new window)

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
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We have read with interest the letter by Tirgan et al.1 on a group of 17 patients with keloids referred for treatment with dupilumab, according to authors with minimal or no response. However, only 8 patients were actually treated with dupilumab for 2–12 months; 3 for 2–3 months, 1 for 6 months and 4 for 10–12 months. The patients that per authors had a possible response was treated for 12 months. The responses were either evaluated by the patients or by the author (MT), with no reporting of how the response was evaluated. In addition to their effect on patients’ appearance, keloids also cause pain and itch.2 Thus, it is imperative to also evaluate for pain, itching and other symptoms in a standardized manner. Of note, evaluations were not standardized as many were self-reported. Last, while dupilumab may have been given to some patients, each received 300 mg subcutaneously every two weeks which may not be enough dosing. Also, treatment duration varied from 2 to 12 months, and often 2 months is not sufficient time to determine clinical response. Responses should be assessed by appropriate measures of dimensions and include itch and pain scores. The pictures included also have different lighting and are difficult to assess. Thus, it is difficult to ascertain response to dupilumab, based on this report. We believe it is necessary to fully assess clinical response to dupilumab in an appropriate placebo-controlled, standardized clinical trial where measures are performed by qualified personnel in the clinic. Further, we are highly experienced in treating skin disorders and know to clinically diagnose keloids and performed a biopsy that was compatible with keloids.3 The areas were biopsied to rule out skin cancer, due to the large growths, as we usually do not biopsy atopic dermatitis lesions. Furthermore, reports such as Klumpar et al.4 report development of keloids in areas of trauma. Our patient had extensive chronic scratching in the popliteal fossa, likely resulting in his keloids and had a family history of keloids.3 Our finding is further validated by a recent report by Nakashima et al.,5 about resolved fibrotic plaques in a patient treated by dupilumab. Our group has also recently shown in 3 keloid patients (compared with controls) that the Th2 immune axis is upregulated in keloid lesional and non-lesional skin.6 These findings, together with our case report and Nakashima et al.,5 provide the rationale to perform an appropriate standardized, placebo-controlled study, with relevant evaluations, and maximal dupilumab dosing (weekly), to establish clinical benefit. We hope that a controlled study, combined with mechanistic assessments, can provide a definitive answer on the clinical benefit of dupilumab and Th2 targeting in keloids. We have thus initiated a large, controlled study, with extensive assessments by a specialized team of researchers and clinicians, for patients with significant keloids, which we are hoping will not only provide an answer but may also change the treatment paradigm for patients with keloids and help with the pain caused by this condition.
De Gasparo R, Pedotti M, Simonelli L, Nickl P, Muecksch F, Cassaniti I, Percivalle E, Lorenzi JCC, Mazzola F, Magri D, Michalcikova T, Haviernik J, Honig V, Mrazkova B, Polakova N, Fortova A, Tureckova J, Iatsiuk V, Di Girolamo S, Palus M, Zudova D, Bednar P, Bukova I, Bianchini F, Mehn D, Nencka R, Strakova P, Pavlis O, Rozman J, Gioria S, Sammartino JC, Giardina F, Gaiarsa S, Pan-Hammarstrom Q, Barnes CO, Bjorkman PJ, Calzolai L, Piralla A, Baldanti F, Nussenzweig MC, Bieniasz PD, Hatziioannou T, Prochazka J, Sedlacek R, Robbiani DF, Ruzek D, Varani L
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Publisher Correction: Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice (vol 593, pg 424, 2021) (opens in new window)

NATURE 2021 SEP 2; 597(7874):E2-E2
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Tobin JN, Hower S, D'Orazio BM, de la Gandara MP, Evering TH, Khalida C, Ramachandran J, Gonzalez LJ, Kost RG, Vasquez KS, de Lencastre H, Tomasz A, Coller BS, Vaughan R
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Comparative Effectiveness Study of Home-Based Interventions to Prevent CA-MRSA Infection Recurrence (opens in new window)

ANTIBIOTICS-BASEL 2021 SEP; 10(9):? Article 1105
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Recurrent skin and soft tissue infections (SSTI) caused by Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) or Methicillin-Sensitive Staphylococcus aureus (CA-MSSA) present treatment challenges. This community-based trial examined the effectiveness of an evidence-based intervention (CDC Guidelines, topical decolonization, surface decontamination) to reduce SSTI recurrence, mitigate household contamination/transmission, and improve patient-reported outcomes. Participants (n = 186) were individuals with confirmed MRSA(+)/MSSA(+) SSTIs and their household members. During home visits; Community Health Workers/Promotoras provided hygiene instructions; a five-day supply of nasal mupirocin; chlorhexidine for body cleansing; and household disinfecting wipes (Experimental; EXP) or Usual Care Control (UC CON) pamphlets. Primary outcome was six-month SSTI recurrence from electronic health records (EHR). Home visits (months 0; 3) and telephone assessments (months 0; 1; 6) collected self-report data. Index patients and participating household members provided surveillance culture swabs. Secondary outcomes included household surface contamination; household member colonization and transmission; quality of life; and satisfaction with care. There were no significant differences in SSTI recurrence between EXP and UC in the intent-to-treat cohort (n = 186) or the enrolled cohort (n = 119). EXP participants showed reduced but non-significant colonization rates. EXP and UC did not differ in household member transmission, contaminated surfaces, or patient-reported outcomes. This intervention did not reduce clinician-reported MRSA/MSSA SSTI recurrence. Taken together with other recent studies that employed more intensive decolonization protocols, it is possible that a promotora-delivered intervention instructing treatment for a longer or repetitive duration may be effective and should be examined by future studies.
Chan TC, Lee MS, Huang WC, Chang WY, Krueger JG, Tsai TF
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Capsaicin attenuates imiquimod-induced epidermal hyperplasia and cutaneous inflammation in a murine model of psoriasis (opens in new window)

BIOMEDICINE & PHARMACOTHERAPY 2021 SEP; 141(?):? Article 111950
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Psoriasis is one of the most common chronic inflammatory diseases that is characterized by well-defined erythematous plaques, with typical histopathological findings of lymphocytic infiltration and epidermal hyperplasia. Topical treatments of psoriasis are either associated with limited response or with side effects. Up to date, topicals targeting neuroimmune axis in psoriasis or psoriasiform dermatitis have not been explored. Here, we investigated whether percutaneous delivery of capsaicin could attenuate the pathological change of psoriasiform inflammation. Imiquimod-induced psoriasis-like murine model was used to evaluate therapeutic effects from topical application of capsaicin. An additional model of psoriasiform dermatitis induced by direct IL-23 injection was used to identify the level of action from capsaicin in this neuroimmune axis. Cutaneous inflammation was assessed by erythema level and ear thickness change. Key cytokines, infiltrating cells in the skin, and draining lymph node cells were investigated. The results showed that capsaicin administration obstructed the activation of IL-23/IL-17 pathway induced by imiquimod, presenting with significantly reduced psoriasiform dermatitis both in gross appearance and microscopic features. Tissue gene expression of psoriatic core cytokines induced by imiquimod (including IL-23, IL-17A, IL-22, TNF-alpha, and IL-6) were greatly decreased by capsaicin application. This protective effect from capsaicin could be hampered by direct intradermal injection of IL-23. Conclusion: Epicutaneous delivery of capsaicin on imiquimod-treated murine skin could significantly decrease expression of multiple inflammatory cytokines and the severity of prototypic change of psoriasiform inflammation. The beneficial effect imposed by capsaicin reinforces the neuroimmune contribution towards psoriasiform inflammation and provides a potential non-steroidal therapeutic alternative for topical treatment of psoriasiform dermatitis.
Racine-Brzostek SE, Karbaschi M, Gaebler C, Klasse PJ, Yee J, Caskey M, Yang HS, Hao Y, Sukhu A, Rand S, Chadburn A, Shi YY, Zuk R, Nussenzweig MC, Cushing MM, Zhao Z
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TOP-Plus Is a Versatile Biosensor Platform for Monitoring SARS-CoV-2 Antibody Durability (opens in new window)

CLINICAL CHEMISTRY 2021 SEP; 67(9):1249-1258
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BACKGROUND: Low initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers dropping to undetectable levels within months after infection have raised concerns about long-term immunity. Both the antibody levels and the avidity of the antibody-antigen interaction should be examined to understand the quality of the antibody response. METHODS: A testing-on-a-probe "plus" panel (TOPPlus) was developed to include a newly developed avidity assay built into the previously described SARS-CoV2 TOP assays that measured total antibody (TAb), surrogate neutralizing antibody (SNAb), IgM, and IgG on a versatile biosensor platform. TAb and SNAb levels were compared with avidity in previously infected individuals at 1.3 and 6.2 months after infection in paired samples from 80 patients with coronavirus disease 2019 (COVID-19). Sera from individuals vaccinated for SARS-CoV-2 were also evaluated for antibody avidity. RESULTS: The newly designed avidity assay in this TOP panel correlated well with a reference Bio-Layer Interferometry avidity assay (r = 0.88). The imprecision of the TOP avidity assay was <10%. Although TAb and neutralization activity (by SNAb) decreased between 1.3 and 6.2 months after infection, the antibody avidity increased significantly (P< 0.0001). Antibody avidity in 10 SARS-CoV-2 vaccinated individuals (median: 28 days after vaccination) was comparable to the measured antibody avidity in infected individuals (median: 26 days after infection). CONCLUSIONS: This highly precise and versatile TOPPlus panel with the ability to measure SARS-CoV-2 TAb, SNAb, IgG, and IgM antibody levels and avidity of individual sera on one sensor can become a valuable asset in monitoring not only patients infected with SARS-CoV-2 but also the status of individuals' COVID-19 vaccination response.
Jette CA, Cohen AA, Gnanapragasam PNP, Muecksch F, Lee YE, Huey-Tubman KE, Schmidt F, Hatziioannou T, Bieniasz PD, Nussenzweig MC, West AP, Keeffe JR, Bjorkman PJ, Barnes CO
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Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies (opens in new window)

CELL REPORTS 2021 SEP 28; 36(13):? Article 109760
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Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (ACE2) binding site on viral spike receptor-binding domains (RBDs). Potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but moreconserved, cryptic epitope could recognize newly emergent zoonotic sarbecoviruses and variants, but they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (COVID-19) donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding and CDRH3-RBD main-chain H-bond interactions that extend an RBD beta sheet, thus reducing sensitivity to RBD side-chain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.
Butelman ER, Chen CY, Brown KG, Lake KJ, Kreek MJ
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Age of onset of heaviest use of cannabis or alcohol in persons with severe opioid or cocaine use disorders (opens in new window)

DRUG AND ALCOHOL DEPENDENCE 2021 SEP 1; 226(?):? Article 108834
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Background: Persons with severe opioid or cocaine use disorders are particularly vulnerable to morbidity and mortality. Heaviest use of mu-opioid receptor agonists and cocaine typically commences in early adulthood and is preceded by substantial adolescent exposure to cannabis and/or alcohol. Little information exists on the age trajectories of exposure to cannabis or alcohol in persons diagnosed with severe opioid or cocaine use disorders, compared to persons diagnosed with other substance use disorders (unrelated to opioids or cocaine). Method: This observational study had n = 854 volunteers (male = 581, female = 273; >= 18 years of age at the time of interview) and examined the ages of onset of heaviest use of cannabis and alcohol in persons diagnosed by DSM-IV criteria with opioid dependence (OD), both opioid and cocaine dependence (OD + CD) and cocaine dependence (CD). These age trajectory measures were compared to persons with other substance use disorders (primarily cannabis and alcohol use disorders, termed "Any Other Diagnoses"). Results: Unadjusted survival analyses showed persons diagnosed with either OD + CD or CD had earlier onset of heaviest use of cannabis (mean ages of 16.2 and 17.8, respectively) compared to the "Any Other Diagnoses" reference group (mean age = 19.5). A multivariate logistic regression showed that later onset of heaviest use of cannabis was associated with lower odds of being in the OD + CD or CD groups, when compared to the reference group. Conclusions: Persons diagnosed with severe cocaine use disorders or dual opioid and cocaine use disorders exhibit a pattern of heavy and especially early adolescent exposure to cannabis, compared to persons with other substance use disorders.
von Beeren C, Bruckner A, Hoenle PO, Ospina-Jara B, Kronauer DJC, Bluthgen N
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Multiple phenotypic traits as triggers of host attacks towards ant symbionts: body size, morphological gestalt, and chemical mimicry accuracy (opens in new window)

FRONTIERS IN ZOOLOGY 2021 SEP 19; 18(1):? Article 46
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Background Ant colonies are plagued by a diversity of arthropod guests, which adopt various strategies to avoid or to withstand host attacks. Chemical mimicry of host recognition cues is, for example, a common integration strategy of ant guests. The morphological gestalt and body size of ant guests have long been argued to also affect host hostility, but quantitative studies testing these predictions are largely missing. We here evaluated three guest traits as triggers of host aggression-body size, morphological gestalt, and accuracy in chemical mimicry-in a community of six Eciton army ant species and 29 guest species. We quantified ant aggression towards 314 guests in behavioral assays and, for the same individuals, determined their body size and their accuracy in mimicking ant cuticular hydrocarbon (CHC) profiles. We classified guests into the following gestalts: protective, myrmecoid, staphylinid-like, phorid-like, and larval-shaped. We expected that (1) guests with lower CHC mimicry accuracy are more frequently attacked; (2) larger guests are more frequently attacked; (3) guests of different morphological gestalt receive differing host aggression levels. Results Army ant species had distinct CHC profiles and accuracy of mimicking these profiles was variable among guests, with many species showing high mimicry accuracy. Unexpectedly, we did not find a clear relationship between chemical host similarity and host aggression, suggesting that other symbiont traits need to be considered. We detected a relationship between the guests' body size and the received host aggression, in that diminutive forms were rarely attacked. Our data also indicated that morphological gestalt might be a valuable predictor of host aggression. While most ant-guest encounters remained peaceful, host behavior still differed towards guests in that ant aggression was primarily directed towards those guests possessing a protective or a staphylinid-like gestalt. Conclusion We demonstrate that CHC mimicry accuracy does not necessarily predict host aggression towards ant symbionts. Exploitation mechanisms are diverse, and we conclude that, besides chemical mimicry, other factors such as the guests' morphological gestalt and especially their body size might be important, yet underrated traits shaping the level of host hostility against social insect symbionts.
Rand DA, Raju A, Saez M, Corson F, Siggia ED
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Geometry of gene regulatory dynamics (opens in new window)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2021 SEP 21; 118(38):? Article e2109729118
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Embryonic development leads to the reproducible and ordered appearance of complexity from egg to adult. The successive differentiation of different cell types that elaborate this complexity results from the activity of gene networks and was likened by Waddington to a flow through a landscape in which valleys represent alternative fates. Geometric methods allow the formal representation of such landscapes and codify the types of behaviors that result from systems of differential equations. Results from Smale and coworkers imply that systems encompassing gene network models can be represented as potential gradients with a Riemann metric, justifying the Waddington metaphor. Here, we extend this representation to include parameter dependence and enumerate all three-way cellular decisions realizable by tuning at most two parameters, which can be generalized to include spatial coordinates in a tissue. All diagrams of cell states vs. model parameters are thereby enumerated. We unify a number of standard models for spatial pattern formation by expressing them in potential form (i.e., as topographic elevation). Turing systems appear nonpotential, yet in suitable variables the dynamics are low dimensional and potential. A time-independent embedding recovers the original variables. Lateral inhibition is described by a saddle point with many unstable directions. A model for the patterning of the Drosophila eye appears as relaxation in a bistable potential. Geometric reasoning provides intuitive dynamic models for development that are well adapted to fit time-lapse data.
Guo YT, Li J, Islam MS, Yan T, Zhou Y, Liang L, Connerton IF, Deng K, Li JQ
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Application of a novel phage vB_SalS-LPSTLL for the biological control of Salmonella in foods (opens in new window)

FOOD RESEARCH INTERNATIONAL 2021 SEP; 147(?):? Article 110492
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Salmonella is one of the most common foodborne pathogens around the world. Phages are envisioned as a new strategy to control foodborne pathogenic bacteria and food safety. A Salmonella specific lytic phage vB_SalSLPSTLL (LPSTLL) was selected for food applications on the basis of lytic range, lytic efficiency, functional stability and characteristics. Phage LPSTLL was able to lyse 11 Salmonella serotypes, which represents the broadest range reported Salmonella phages, and was able to suppress the growth of Salmonella enterica in liquid culture over nine hours. LPSTLL exhibited rapid reproductive activity with a short latent period and a large burst size in one-step growth experiment. LPSTLL remained active over a pH range of 3.0 to 12.0, and at incubation temperatures up to 60 degrees C for 60 min, indicating wide applicability for food processing and storage. Significant reductions of viable Salmonella were observed in diverse foods (milk, apple juice, chicken and lettuce) with reductions up to 2.8 log CFU/mL recorded for milk. Sensory evaluation indicated that treatment with phage LPSTLL did not alter the visual or tactile quality of food matrices. Genome analysis of LPSTLL indicated the absence of any virulence or antimicrobial resistance genes. Genomic comparisons suggest phage LPSTLL constitutes a novel member of a new genus, the LPSTLLvirus with the potential for Salmonella biocontrol in the food industry.