A case for associational resistance: Apparent support for the stress gradient hypothesis varies with study system.

According to the stress gradient hypothesis (SGH), ecological interactions between organisms shift positively as environmental stress increases. In the case of associational resistance, habitat is modified to ameliorate stress, benefitting other organisms. The SGH is contentious due to conflicting evidence and theoretical perspectives, so we adopted a meta-analytic approach to determine if it is widely supported across a variety of contexts, including different kingdoms, ecosystems, habitats, interactions, stressors, and life history stages. We developed an extensive list of Boolean search criteria to search the published ecological literature and successfully detect studies that both directly tested the hypothesis, and those that were relevant but never mentioned it. We found that the SGH is well supported by studies that feature bacteria, plants, terrestrial ecosystems, interspecific negative interactions, adults, survival instead of growth or reproduction, and drought, fire, and nutrient stress. We conclude that the SGH is indeed a broadly relevant ecological hypothesis that is currently held back by cross-disciplinary communication barriers. More SGH research is needed beyond the scope of interspecific plant competition, and more SGH research should feature multifactor stress. There remains a need to account for positive interactions in scientific pursuits, such as associational resistance in tests of the SGH.

Differences in IgG Antibody Responses following BNT162b2 and mRNA-1273 SARS-CoV-2 Vaccines.

Studies examining antibody responses by vaccine brand are lacking and may be informative for optimizing vaccine selection, dosage, and regimens. The purpose of this study is to assess IgG antibody responses following immunization with BNT162b2 (30 µg mRNA) and mRNA-1273 (100 µg mRNA) vaccines. A cohort of clinicians at a nonprofit organization is being assessed clinically and serologically following immunization with BNT162b2 or mRNA-1273. IgG responses were measured at the Remington Laboratory by an IgG assay against the SARS-CoV-2 spike protein-receptor binding domain. Mixed-effect linear (MEL) regression modeling was used to examine whether the SARS-CoV-2 IgG level differed by vaccine brand, dosage, or number of days since vaccination. Among 532 SARS-CoV-2 seronegative participants, 530 (99.6%) seroconverted with either vaccine. After adjustments for age and gender, MEL regression modeling revealed that the average IgG antibody level increased after the second dose compared to the first dose (P < 0.001). Overall, titers peaked at week 6 for both vaccines. Titers were significantly higher for the mRNA-1273 vaccine on days 14 to 20 (P < 0.05), 42 to 48 (P < 0.01), 70 to 76 (P < 0.05), and 77 to 83 (P < 0.05) and higher for the BNT162b2 vaccine on days 28 to 34 (P < 0.001). In two participants taking immunosuppressive drugs, the SARS-CoV-2 IgG antibody response remained negative. mRNA-1273 elicited higher IgG antibody responses than BNT162b2, possibly due to the higher S-protein delivery. Prospective clinical and serological follow-up of defined cohorts such as this may prove useful in determining antibody protection and whether differences in antibody kinetics between the vaccines have manufacturing relevance and clinical significance. IMPORTANCE SARS-CoV-2 vaccines using the mRNA platform have become one of the most powerful tools to overcome the COVID-19 pandemic. mRNA vaccines enable human cells to produce and present the virus spike protein to their immune system, leading to protection from severe illness. Two mRNA vaccines have been widely implemented, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech). We found that, following the second dose, spike protein antibodies were higher with mRNA-1273 than with BNT162b2. This is biologically plausible, since mRNA-1273 delivers a larger amount of mRNA (100 µg mRNA) than BNT162b2 (30 µg mRNA), which is translated into spike protein. This difference may need to be urgently translated into changes in the manufacturing process and dose regimens of these vaccines.

Statins and "chameleon-like" cutaneous eruptions: simvastatin-induced acral cutaneous vesiculobullous and pustular eruption in a 70-year-old man.

BACKGROUND: The statin medications for lowering of blood cholesterol can be associated with cutaneous lichenoid reactions but also a variety of other adverse cutaneous eruptions, including Stevens-Johnson syndrome, toxic epidermolytic necrolysis, porphyria cutanea tarda, linear IgA bullous dermatosis, and reaction patterns (lupus and dermatomyositis-like and pustular). Cutaneous eruptions ("eczema" in the product literature) owing to simvastatin are reported in approximately 1.5% individuals compared with placebo. OBJECTIVE: To correlate the clinical and microscopic features of an unusual vesiculobullous reaction to simvastatin. METHODS: Retrospective analysis of clinical information and skin biopsies. RESULTS: We present the case of a 70-year-old man with chronic vesiculobullous and pustular annular lesions on distal arms, legs, hands, and feet for 2 years. The eruption was recalcitrant to potent topical corticosteroids. Multiple biopsies at different times showed a spongiotic and lichenoid hypersensitivity reaction resembling contact dermatitis, purpuric drug eruption, and pustular folliculitis. The common themes in the histopathology were spongiosis with microvesiculation, focal lichenoid infiltrates, dermal hemorrhage, and chronic superficial inflammatory cell infiltrates with eosinophils. The eruption began when simvastatin was started, improved when it was stopped, recurred with rechallenge, and cleared when simvastatin was discontinued. CONCLUSIONS: Acral cutaneous vesiculobullous eruption is an uncommon adverse drug eruption due to simvastatin, one of many different patterns possible. A high level of suspicion for an unexplained cutaneous eruption in an older individual on statins is important to identification of the disorder and discontinuation of the offending medication.

Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia.

The tumor necrosis factor alpha receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH(2)-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers.

Use of human tissue to assess the oncogenic activity of melanoma-associated mutations.

Multiple genetic alterations occur in melanoma, a lethal skin malignancy of increasing incidence. These include mutations that activate Ras and two of its effector cascades, Raf and phosphoinositide 3-kinase (PI3K). Induction of Ras and Raf can be caused by active N-Ras and B-Raf mutants as well as by gene amplification. Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification. Melanomas also commonly show impairment of the p16(INK4A)-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways. CDKN2A mutations can produce p16(INK4A) and ARF protein loss. Rb bypass can also occur through activating CDK4 mutations as well as by CDK4 amplification. In addition to ARF deletion, p53 pathway disruption can result from dominant negative TP53 mutations. TERT amplification also occurs in melanoma. The extent to which these mutations can induce human melanocytic neoplasia is unknown. Here we characterize pathways sufficient to generate human melanocytic neoplasia and show that genetically altered human tissue facilitates functional analysis of mutations observed in human tumors.

Melanoma genetics and the development of rational therapeutics.

Melanoma is a cancer of the neural crest-derived cells that provide pigmentation to skin and other tissues. Over the past 4 decades, the incidence of melanoma has increased more rapidly than that of any other malignancy in the United States. No current treatments substantially enhance patient survival once metastasis has occurred. This review focuses on recent insights into melanoma genetics and new therapeutic approaches being developed based on these advances.

Aggressive cutaneous T-cell lymphomas after TNFalpha blockade.

Pharmacologic blockade of TNFalpha has been a highly effective approach to treating several immunologically mediated diseases, including rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. 1,2,3 Both etanercept, the recombinant extracellular domain of the tumor necrosis factor receptor 2 (TNFR2), and infliximab, a humanized murine antibody, bind TNFalpha and block its interaction with cell surface receptors. Recently, it has become clear that blockade of TNFalpha action is profoundly immunosuppressive, and may result in reactivation of tuberculosis and histoplasmosis, as well as the emergence of B-cell lymphomas. 4,5,6 In this report, we describe two cases of cutaneous and systemic T-cell lymphoma that progressed rapidly in the setting of TNFalpha blockade. Both cases were characterized by rapid onset, a fulminant clinical course with extensive cutaneous and systemic involvement, and death within months of diagnosis.