Bronchioalveolar organoids: A preclinical tool to screen toxicity associated with antibody-drug conjugates.

Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.

Influence of Walking Over Unexpected Uneven Terrain on Joint Loading for Individuals With Transtibial Amputation.

Individuals with transtibial amputation (TTA) experience asymmetric lower-limb loading which can lead to joint pain and injuries. However, it is unclear how walking over unexpected uneven terrain affects their loading patterns. This study sought to use modeling and simulation to determine how peak joint contact forces and impulses change for individuals with unilateral TTA during an uneven step and subsequent recovery step and how those patterns compare to able-bodied individuals. We expected residual limb loading during the uneven step and intact limb loading during the recovery step would increase relative to flush walking. Further, individuals with TTA would experience larger loading increases compared to able-bodied individuals. Simulations of individuals with TTA showed during the uneven step, changes in joint loading occurred at all joints except the prosthetic ankle relative to flush walking. During the recovery step, intact limb joint loading increased in early stance relative to flush walking. Simulations of able-bodied individuals showed large increases in ankle joint loading for both surface conditions. Overall, increases in early stance knee joint loading were larger for those with TTA compared to able-bodied individuals during both steps. These results suggest that individuals with TTA experience altered joint loading patterns when stepping on uneven terrain. Future work should investigate whether an adapting ankle-foot prosthesis can mitigate these changes to reduce injury risk.

Fractional CO2 laser treatment as adjunctive therapy to topical steroids for managing vulvar lichen sclerosus.

OBJECTIVES: Uncontrolled vulvar lichen sclerosus (VLS) is often associated with distressful symptoms of genital itch, irritation, and pain and can lead to a pathological process including anatomical changes, scarring, and an elevated risk of cancer in the genital area. First-line topical corticosteroid as monotherapy is frequently not adequate to fully suppress disease activity and control symptoms. This study evaluated the efficacy of fractional CO2 laser treatments as adjunctive therapy where recalcitrant VLS had been improved, but not adequately controlled, with topical corticosteroid treatment. Outcomes were evaluated up to 12 months after a series of CO2 laser treatments delivered via a fractional handpiece. MATERIALS AND METHODS: Women with a diagnosis of VLS supported by histologic findings on biopsy and/or clinical signs on physical examination received up to five monthly laser treatments. Subjects maintained existing topical corticosteroid and any exogenous hormone treatment during the study. Investigators assessed severity (0 = not present, 1 = mild, 2 = moderate, or 3 = severe) of clinical signs and architectural changes present before adjunctive study interventions and at follow-up visits. Subjects reported the presence of clinical symptoms and impact on quality of life on 4- or 5-point Likert scales. The validated Female Sexual Function Index (FSFI) was used to assess changes in sexual function. Four subjects were biopsied before adjunctive laser treatment and at follow-up. RESULTS: Twelve females, 11 postmenopausal, with a mean age of 57 ± 10 years received three to five monthly CO2 laser treatments. Significant improvement in all prominent clinical signs and architectural changes were reported at the 3- and 6-month follow-ups after the treatment series. Significant improvement was maintained at the 12-month follow-up, with 89% of subjects showing at least one-point improvement in elasticity compared to baseline; 86% in lichenification; 88% in sclerosis; and 80% in whitening and parchment-like skin. Labial fusion and the extent of disease improved in 50% of patients. Ulcerations present in three subjects at baseline resolved after treatment. Subjects reported 86% improvement in dyspareunia and 83% in skin tearing. Quality of life improved significantly after treatment (p < 0.01). The 6-month follow-up FSFI showed significant improvement in sexual function compared to baseline (p < 0.05), with a mean point improvement of 4.5. Histology findings after treatment showed some positive improvement, as a decrease in dermal hyalinized zone thickness. There were no treatment complications or adverse events related to the treatment. CONCLUSIONS: Fractional CO2 laser treatment outcomes showed improvement in predominant clinical signs and architectural changes in VLS recalcitrant to topical corticosteroid treatment. Adjunctive laser treatment relieved symptoms and improved quality of life as well as sexual function. Fractional CO2 laser treatment may provide an advanced treatment modality for the management of recalcitrant VLS with improved patient care and sustainable outcomes. Further study in a larger population and with CO2 laser treatment to both vulvar tissue and the vaginal canal should be explored.

Shifting paradigms in restoration of the world's coral reefs.

Many ecosystems around the world are rapidly deteriorating due to both local and global pressures, and perhaps none so precipitously as coral reefs. Management of coral reefs through maintenance (e.g., marine-protected areas, catchment management to improve water quality), restoration, as well as global and national governmental agreements to reduce greenhouse gas emissions (e.g., the 2015 Paris Agreement) is critical for the persistence of coral reefs. Despite these initiatives, the health and abundance of corals reefs are rapidly declining and other solutions will soon be required. We have recently discussed options for using assisted evolution (i.e., selective breeding, assisted gene flow, conditioning or epigenetic programming, and the manipulation of the coral microbiome) as a means to enhance environmental stress tolerance of corals and the success of coral reef restoration efforts. The 2014-2016 global coral bleaching event has sharpened the focus on such interventionist approaches. We highlight the necessity for consideration of alternative (e.g., hybrid) ecosystem states, discuss traits of resilient corals and coral reef ecosystems, and propose a decision tree for incorporating assisted evolution into restoration initiatives to enhance climate resilience of coral reefs.

Pathogen-induced expression of a blight tolerance transgene in American chestnut.

American chestnut (Castanea dentata) is a susceptible host of the invasive necrotrophic fungus Cryphonectria parasitica, which causes chestnut blight disease. The fungal pathogen attacks chestnut stems by invading wounded tissue and secreting oxalate. This process leads to the death of infected host cells and the formation of cankers, eventually girdling stems and killing the tree above the infections. To reduce damage caused by fungal oxalate, American chestnut has been genetically engineered to express a wheat oxalate oxidase (OxO). This enzyme degrades the oxalate produced by the pathogen and confers elevated tolerance to Cryphonectria parasitica infection. We report new lines of transgenic American chestnut that have been developed with the win3.12 inducible promoter from poplar (Populus deltoides) driving OxO expression. This promoter is responsive to both wounding and pathogen infection, with a low level of baseline expression. Targeted expression of OxO to wounded and infected tissue is sought as an alternative to constitutive expression for potential metabolic resource conservation and transgene stability over the long lifetime of a tree and over successive generations of breeding. Transgenic Castanea dentata lines harbouring the win3.12-OxO construct were evaluated for transgene expression patterns and tolerance to chestnut blight infection. OxO transcript levels were low in uninfected plants, but robust infection-induced expression levels were observed, with one transgenic line reaching levels comparable to those of previously characterized CaMV35S-OxO lines. In chestnut blight infection bioassays, win3.12-OxO lines showed elevated disease tolerance similar to blight-resistant Chinese chestnut (Castanea mollissima) controls.

A Clinical Approach to Vulvar Ulcers.

This article discusses the differential diagnosis of vulvar ulcers and describes a general clinical approach to this common but nonspecific examination finding. The differential diagnosis includes sexually and nonsexually transmitted infections, dermatitides, trauma, neoplasms, hormonally induced ulcers, and drug reactions. Patient history and physical examination provide important clues to the cause of a vulvar ulcer. However, laboratory testing is usually required for accurate diagnosis because the clinical presentation is often nonspecific and may be atypical due to secondary conditions.

Challenging Ulcerative Vulvar Conditions: Hidradenitis Suppurativa, Crohn Disease, and Aphthous Ulcers.

This article discusses the clinical evaluation and approach to patients with 3 complex ulcerative vulvar conditions: hidradenitis suppurativa, metastatic Crohn disease of the vulva, and aphthous ulcers. These conditions are particularly challenging to medical providers because, although each is known to present with nonspecific examination findings that vary in morphology, the predominance of the diagnosis is based on clinical examination and exclusion of a wide variety of other conditions. Care of patients with these conditions is further complicated by the lack of therapeutic data and the significant impact these conditions have on quality of life.

Design and synthesis of DNA-tethered ruthenium complexes that self-assemble into linear arrays.

Ruthenium(II) bis(terpyridine) complexes have been prepared with two triethylene glycol linkers to which DNA sequences have been attached; hybridization at various complex ratios results in linear arrays of varying lengths.

The effects of music therapy on vital signs, feeding, and sleep in premature infants.

OBJECTIVES: Recorded music risks overstimulation in NICUs. The live elements of music such as rhythm, breath, and parent-preferred lullabies may affect physiologic function (eg, heart and respiratory rates, O2 saturation levels, and activity levels) and developmental function (eg, sleep, feeding behavior, and weight gain) in premature infants. METHODS: A randomized clinical multisite trial of 272 premature infants aged ≥32 weeks with respiratory distress syndrome, clinical sepsis, and/or SGA (small for gestational age) served as their own controls in 11 NICUs. Infants received 3 interventions per week within a 2-week period, when data of physiologic and developmental domains were collected before, during, and after the interventions or no interventions and daily during a 2-week period. RESULTS: Three live music interventions showed changes in heart rate interactive with time. Lower heart rates occurred during the lullaby (P < .001) and rhythm intervention (P = .04). Sucking behavior showed differences with rhythm sound interventions (P = .03). Entrained breath sounds rendered lower heart rates after the intervention (P = .04) and differences in sleep patterns (P < .001). Caloric intake (P = .01) and sucking behavior (P = .02) were higher with parent-preferred lullabies. Music decreased parental stress perception (P < .001). CONCLUSIONS: The informed, intentional therapeutic use of live sound and parent-preferred lullabies applied by a certified music therapist can influence cardiac and respiratory function. Entrained with a premature infant's observed vital signs, sound and lullaby may improve feeding behaviors and sucking patterns and may increase prolonged periods of quiet-alert states. Parent-preferred lullabies, sung live, can enhance bonding, thus decreasing the stress parents associate with premature infant care.

Clinical care of vulvar pruritus, with emphasis on one common cause, lichen simplex chronicus.

Vulvar pruritus is a common and distressing condition for patients, and its presentation is often delayed and complicated by home remedies. The true prevalence cannot be accurately estimated. Vulvar pruritus is a symptom, and an underlying cause must be sought and not assumed. This is best accomplished by obtaining a careful history of vulvar care regimens and treatments, performing a detailed physical examination, and considering a broad differential diagnosis. This article provides a practical and clinical approach to the evaluation of vulvar pruritus and then focuses specifically on one common cause, lichen simplex chronicus.

Four-arm oligonucleotide Ni(II)-cyclam-centered complexes as precursors for the generation of supramolecular periodic assemblies.

The development of a multiarm metal-centered DNA building block as a precursor for the construction of supramolecular assemblies has relied upon the preparation of a Ni(II)-1,4,8,11-tetrazacyclotetradecane ligand (cyclam) functionalized with four linkers. This complex can be incorporated into a support-bound DNA sequence and the remaining three linkers can then be elongated by DNA synthesis. The result is a Ni(II)-cyclam complex tethering four 20-mer DNA strands. This building block, designed to be tetrahedral in nature, can in principle be used to form tetrahedral assemblies. These assemblies can be designed to be of known size and composition or permitted to grow into complexes of essentially infinite size, ideally the macroscopic version of a crystal.