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"Yale J Biol Med"[jour]
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1.
Yale J Biol Med. 2020 Mar 27;93(1):221-223. eCollection 2020 Mar.
Learning from a Trailblazer in Dermatology: An Interview with Jean Bolognia, MD.
KEYWORDS:
dermatology
- PMID:
- 32226351
2.
Yale J Biol Med. 2020 Mar 27;93(1):215-219. eCollection 2020 Mar.
Race and Genetics: Somber History, Troubled Present.
Abstract
Following the completion of the Human Genome Project (HGP) in 2003, advances in DNA sequencing technologies further popularized the field of genomics and brought its social ramifications to the fore. Scholars across disciplines recently voiced serious concerns about the re-emergence of genomic research that might be used to justify racism. In this piece, I trace the history of attempts to biologize the concept of race and its diffused presence in today's genomic research. I then include a brief analysis inspired by concepts from the field of Science and Technology Studies (STS) to suggest selected ways to produce better scientific knowledge. The text highlights historic landmarks of interest to science practitioners curious about the ways science of the past co-shapes science of the present. I then argue that science has never been isolated from the socio-political climate it is produced in; instead, it has been morphed by its surroundings and historically used as a potent tool to justify systemic oppression.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
genetics; genomics; race; racial science; racism; scientific racism
- PMID:
- 32226350
3.
Yale J Biol Med. 2020 Mar 27;93(1):207-213. eCollection 2020 Mar.
Melanoma Radiological Surveillance: A Review of Current Evidence and Clinical Challenges.
Abstract
Melanoma is a common cancer in both young and older populations in many western countries. Rates of melanoma diagnosis worldwide are increasing. With the introduction of both targeted and immunotherapies there have been dramatic improvements in the care of patients with metastatic melanoma. With these new therapies being increasingly offered to patients with stage III metastatic melanoma and stage IV disease, radiological surveillance of melanoma has become a widely used method of monitoring melanoma patients for early locoregional and distant metastasis. However, concerns have been raised about risk of false positive results, which patients to consider radiological surveillance for, and at what intervals to do so. To date, there are no published review articles on the topic of radiological surveillance in melanoma patients identified in the MEDLINE database. A comprehensive literature review was performed by searching the MEDLINE database to review all published works on this topic. This article aims to present an extensive review of literature surrounding radiological surveillance in melanoma patients, a discussion of controversies, and recommendations for surveillance modalities.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
CT; MRI; PET; follow-up; melanoma; surveillance; ultrasound
- PMID:
- 32226349
4.
Yale J Biol Med. 2020 Mar 27;93(1):197-206. eCollection 2020 Mar.
Getting Under the Skin: Targeting Cutaneous Autoimmune Disease.
Abstract
Autoimmune diseases of the skin occur when the immune system attacks normal skin. The immune system can be broadly divided into an effector arm responsible for fighting infections and cancer and a regulatory arm that reduces autoreactivity and maintains immune homeostasis. Cutaneous autoimmunity develops when the equilibrium between the effector arm and regulatory arm of the immune system is disrupted. Recent insights into the inflammatory pathways that are overactive in some cutaneous autoimmune diseases have led to therapies targeting the effector arm of the immune system with greater treatment efficacy than previously used broad immunosuppressants. The current paradigm of inhibiting excessive immune activation for treating cutaneous autoimmunity will be discussed including cytokine blockade, cellular depletion, intracellular signaling blockade and costimulatory blockade. Despite the success of this approach many cutaneous autoimmune diseases lack a clearly delineated pathway to target and therefore new strategies are needed. An emerging therapeutic strategy targeting the regulatory arm of the immune system to induce tolerance and disease remission provides new hope for treating cutaneous autoimmunity. Such an approach includes cellular therapy with regulatory T cells and chimeric autoantibody receptor T cells, cytokine therapy with low-dose interleukin-2, immune checkpoint stimulation, tolerogenic vaccines and microbiome biotherapy. This mini-review will discuss the current and emerging therapeutic strategies for cutaneous autoimmune diseases and provide an organizational framework for understanding distinct mechanisms of action.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
CAAR T cells; CAR T cells; Janus kinase inhibitors; cutaneous autoimmunity; inhibitory receptor stimulation; monoclonal antibodies; novel therapeutics; regulatory T cells; tolerance
- PMID:
- 32226348
5.
Yale J Biol Med. 2020 Mar 27;93(1):187-195. eCollection 2020 Mar.
The Promise of JAK Inhibitors for Treatment of Sarcoidosis and Other Inflammatory Disorders with Macrophage Activation: A Review of the Literature.
Abstract
Certain inflammatory disorders are characterized by macrophage activation and accumulation in tissue; sometimes leading to the formation of granulomas, as in sarcoidosis. These disorders are often difficult to treat and more effective, molecularly targeted therapies are needed. Recent work has shown that overproduction of inflammatory cytokines, such as interferon gamma (IFN-γ) leading to constitutive activation of the JAK-STAT pathway may be a conserved feature of these disorders. Use of JAK inhibitors, which can block these signals, has resulted in dramatic improvement in several patients with sarcoidosis. JAK inhibitors also appear to have activity in other inflammatory disorders with macrophage activation including hemophagocytic lymphohistiocystosis, Crohn's disease, granuloma annulare, and necrobiosis lipoidica. Here, we review the role of JAK dependent cytokines in macrophage activation and granuloma formation and the clinical evidence supporting the use of JAK inhibition in these disorders. Ongoing efforts to evaluate role of JAK inhibitors in these disorders is also discussed.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Crohn’s disease; JAK inhibitor; Janus kinase; granuloma annulare; hemophagocytic lymphohistiocytosis; necrobiosis lipoidica; ruxolitinib; sarcoidosis; tofacitinib
- PMID:
- 32226347
6.
Yale J Biol Med. 2020 Mar 27;93(1):175-185. eCollection 2020 Mar.
Kinin B1 Receptor Signaling in Skin Homeostasis and Wound Healing.
Abstract
Kinins are proinflammatory peptides that are formed in the skin by the enzymatic action of tissue kallikrein (KLK1) on kininogens. Tissue kallikrein is produced by eccrine sweat glands and also by cells of the stratum granulosum and other skin appendages. Kinin formation may be favored during inflammatory skin disorders when plasma constituents, including kininogens, extravasate from venules and capillaries, which have increased permeability in response to the plethora of inflammatory mediators generated in the course of acute inflammation. By activating either kinin B1 or B2 receptors, kinins modulate keratinocyte differentiation, which relays on activation of several signaling systems that follows receptor stimulation. Participation of the kinin B1 receptor in wound healing is still a matter of controversy though some studies indicate that B1 receptor stimulation regulates keratinocyte migration by controlling metalloproteases 2 and 9 production and by improving wound closure in a mouse model. Development of more stable kinin B1 receptor agonists may be beneficial to modulate wound healing, especially if we take into account that the B1 receptor is up-regulated by inflammation and by cytokines generated in the inflamed microenvironment.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
KLK1; kallikrein-related peptidases; kinin B1 receptor; kinin B2 receptor; skin; tissue kallikrein; wound healing
- PMID:
- 32226346
7.
Yale J Biol Med. 2020 Mar 27;93(1):161-173. eCollection 2020 Mar.
Understanding Transcriptional Networks Regulating Initiation of Cutaneous Wound Healing.
Abstract
The epidermis has an essential function in creating a barrier against the external environment to retain proper fluid balance and block the entry of pathogens. When damage occurs to this barrier, the wound must quickly be sealed to avoid fluid loss, cleared of invading pathogens, and then keratinocytes must re-form an intact barrier. This requires complex integration of temporally and spatially distinct signals to execute orderly closure of the wound, and failure of this process can lead to chronic ulceration. Transcription factors serve as a key integration point for the myriad of information coming from the external environment, allowing for an orderly process of re-epithelialization. Importantly, transcription factors engage with and alter the chromatin structure around key target genes through association with different chromatin-modifying complexes. In this review, we will discuss the current understanding of how transcription is regulated during the initiation of re-epithelialization, and the exciting technological advances that will allow for a more refined mechanistic understanding of the re-epithelialization process.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Wound healing; keratinocytes; migration; re-epithelialization; skin; transcription
- PMID:
- 32226345
8.
Yale J Biol Med. 2020 Mar 27;93(1):145-159. eCollection 2020 Mar.
Extracorporeal Photochemotherapy: Mechanistic Insights Driving Recent Advances and Future Directions.
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells, necessary for the initiation and maintenance of antigen-specific immunity and tolerance. Decades of research have been driven by hopes to harness the immunological capabilities of DCs and achieve physiological partnership with the immune system for therapeutic ends. Potential applications for DC-based immunotherapy include treatments for cancer, autoimmune disorders, and infectious diseases. However, DCs have poor availability in peripheral and lymphoid tissues and have poor survivability in culture, leading to the development of multiple strategies to generate and manipulate large numbers of DCs ex vivo. Among these is Extracorporeal Photopheresis (ECP), a widely used cancer immunotherapy. Recent advancements have uncovered that stimulation of monocyte-to-DC maturation via physiologic inflammatory signaling lies at the mechanistic core of ECP. Here, we describe the landscape of DC-based immunotherapy, the historical context of ECP, the current mechanistic understanding of ex vivo monocyte-to-DC maturation in ECP, and the implications of this understanding on making scientifically driven improvements to modern ECP protocols and devices.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Dendritic cell; Extracorporeal photopheresis; Immunotherapy; Platelets
- PMID:
- 32226344
9.
Yale J Biol Med. 2020 Mar 27;93(1):133-143. eCollection 2020 Mar.
Unraveling Immune-Epithelial Interactions in Skin Homeostasis and Injury.
Abstract
The skin serves as a front line of defense against harmful environmental elements and thus is vital for organismal survival. This barrier is comprised of a water-tight epithelial structure reinforced by an arsenal of immune cells. The epithelial and immune components of the skin are interdependent and actively dialogue to maintain health and combat infectious, injurious, and noxious stimuli. Here, we discuss the molecular mediators of this crosstalk that establish tissue homeostasis and their dynamic adaptations to various stress conditions. In particular, we focus on immune-epithelial interactions in homeostatic tissue regeneration, during natural cycling of the hair follicle, and following skin injury. We also highlight the epithelial derived factors that orchestrate immunity. A comprehensive and mechanistic understanding of dynamic interactions between cutaneous immune cells and the epithelium can be leveraged to develop novel therapies to treat of range of skin diseases and boost skin health.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
epithelial stem cells; immune-epithelial interactions; skin immunity; tissue regeneration
- PMID:
- 32226343
10.
Yale J Biol Med. 2020 Mar 27;93(1):123-132. eCollection 2020 Mar.
Cutaneous Toxicities of Immune Checkpoint Inhibitors: The Role of the Dermatologist.
Abstract
The advent of immune checkpoint inhibition represents a paradigm shift in the treatment of an increasing number of cancers. However, the incredible therapeutic promise of immunotherapy brings with it the need to understand and manage its diverse array of potential adverse events. The skin is the most common site of immune-related adverse vents (irAEs), which can present with a wide variety of disparate morphologies and severities. These toxicities can endanger patient health and the ability to continue on therapy. This review summarizes our current understanding of the presentation and management of the most common and clinically significant cutaneous irAEs associated with immune checkpoint inhibitor (ICI) therapy. Effective management of these cutaneous irAEs requires an understanding of their morphology, their appropriate clinical characterization, and their potential prognostic significance. Their treatment is additionally complicated by the desire to minimize compromise of the patient's anti-neoplastic regimen and emphasizes the use of non-immunosuppressive interventions whenever possible. However, though cutaneous irAEs represent a challenge to both oncologist and dermatologist alike, they offer a unique glimpse into the mechanisms that underlie not only carcinogenesis, but many primary dermatoses, and may provide clues to the treatment of disease even beyond cancer.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Dermatology; drug toxicity; immune checkpoint inhibitor; immune related adverse event; oncodermatology; oncology; skin toxicity; supportive oncodermatology
- PMID:
- 32226342
11.
Yale J Biol Med. 2020 Mar 27;93(1):111-121. eCollection 2020 Mar.
Insights Into the Molecular and Cellular Underpinnings of Cutaneous T Cell Lymphoma.
Abstract
Cutaneous T cell lymphoma (CTCL) is a rare malignancy of skin-homing T lymphocytes. Advances in whole exome sequencing have identified a vast number of both single nucleotide variants (SNVs) and genomic copy number alterations (GCNAs) as driver mutations present in CTCL cells. These alterations cluster within several key pathways - T cell/NF-κB/JAK-STAT activation, cell cycle dysregulation/apoptosis, and DNA structural dysregulation affecting gene expression - allowing the maintenance of a population of proliferating, activated malignant T lymphocytes. While much of the clinical spectrum, genetic alterations, and oncogenic behavior of CTCL have been elucidated, little is known about the etiology that underlies CTCL malignant transformation and progression. Herein, we review the epidemiology, clinical presentation, and pathophysiology of CTCL to provide a perspective on CTCL pathogenesis. We outline a series of alterations by which mature, activated T lymphocytes are endowed with apoptosis resistance and cutaneous persistence. Subsequent genomic alterations including the loss of chromosomal structural controls further promote proliferation and constitutive T cell activation. CTCL cells are both malignant cells and highly functional T cells that can have major cutaneous and immunologic effects on the patient, including the suppression of cell-mediated immunity that facilitates malignant cell expansion. A deeper understanding of the molecular and cellular underpinnings of CTCL can help guide clinical management as well as inform prognosis and therapeutic discovery.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
CTCL; Mycosis fungoides; Sézary syndrome; cutaneous T cell lymphoma
- PMID:
- 32226341
12.
Yale J Biol Med. 2020 Mar 27;93(1):97-110. eCollection 2020 Mar.
Current Developments in the Immunology of Psoriasis.
Abstract
Psoriasis is a frequent inflammatory skin disease. Fundamental research on the pathogenesis of psoriasis has substantially increased our understanding of skin immunology, which has helped to introduce innovative and highly effective therapies. Psoriasis is a largely T lymphocyte-mediated disease in which activation of innate immune cells and pathogenic T cells result in skin inflammation and hyperproliferation of keratinocytes. B cells have thus far largely been neglected regarding their role for the pathogenesis of psoriasis. However, recent data shed light on their role in inflammatory skin diseases. Interestingly, interleukin (IL)-10-producing regulatory B cells have been assumed to ameliorate psoriasis. In this review, we will discuss the development of disease, pathogenicity, and current developments in therapeutic options. We describe different roles of T cells, B cells, and cytokines for the immunopathology and disease course of psoriasis.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Biologics; Cytokines; Lymphocytes; Psoriasis; Regulatory B cells
- PMID:
- 32226340
13.
Yale J Biol Med. 2020 Mar 27;93(1):81-95. eCollection 2020 Mar.
Cutaneous Lupus Erythematosus: Current and Future Pathogenesis-Directed Therapies.
Abstract
Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin with significant morbidity. Current treatments are often inadequate to control disease and there are no Food and Drug Administration (FDA)-approved therapies for this potentially debilitating disease, underscoring an unmet medical need. Recent insights into disease pathogenesis have implicated innate and adaptive immune components, including type I and type III interferons in the development of CLE. Promising clinical trials based on these insights are now underway. However, the full spectrum of immune cells, cytokines, and environmental triggers contributing to disease remain to be elucidated. In this review, we will highlight the current understanding of CLE immunopathogenesis, the ongoing clinical trial landscape, and provide a framework for designing future therapeutic strategies for CLE based on new insights into disease pathogenesis.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
cutaneous lupus erythematosus; discoid lupus; systemic lupus erythematosus
- PMID:
- 32226339
14.
Yale J Biol Med. 2020 Mar 27;93(1):69-80. eCollection 2020 Mar.
Recent Advances in Studies of Skin Color and Skin Cancer.
LaBerge GS1,2, Duvall E2, Grasmick Z3, Haedicke K4, Galan A5, Leverett J6, Baswan S6, Yim S6, Pawelek J5.
Abstract
The relationship between skin color and skin cancer is well established: the less melanin in one's skin the greater the risk for developing skin cancer. This review is in two parts. First, we summarize the current understanding of the cutaneous pigmentary system and trace melanin from its synthesis in the pigment cell melanosomes through its transfer to keratinocytes. We also present new methods for reducing melanin content in hyper-pigmented areas of skin such as solar lentigenes, melasma, and post-inflammatory hyperpigmentation. Second, we present evidence that at least one mechanism for the development of metastatic melanoma and other solid tumors is fusion and hybridization of leucocytes such as macrophages with primary tumor cells. In this scenario, hybrid cells express both the chemotactic motility of the leucocyte and the de-regulated cell division of the tumor cell, causing the cells to migrate a deadly journey to lymph nodes, distant organs, and tissues.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
cytidine as melanin inhibitor; leucocyte-tumor cell hybrids; melanin transfer; skin cancer; skin color
- PMID:
- 32226338
15.
Yale J Biol Med. 2020 Mar 27;93(1):55-67. eCollection 2020 Mar.
Cutaneous Photoprotection: A Review of the Current Status and Evolving Strategies.
Abstract
Ultraviolet radiation (UVR) exposure is well established as the major environmental risk factor for the development of melanoma, cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). Additional risk factors including genetic mutations, other environmental agents, and immune status are important in modulating the effects of UVR. Dermatologists advocate a multi-pronged approach to minimizing UVR exposure including lifestyle modifications, UVR protective clothing, and topically applied sun-protective products, i.e. sunscreen. New Federal Drug Administration (FDA) regulations on sunscreen have brought certain long-standing ingredients in sunscreen products under scrutiny. The FDA's proposed rule for over the counter (OTC) monograph states that the inorganic sunscreens, zinc oxide and titanium dioxide, were found to be "generally recognized as safe and effective," but cite insufficient evidence to grant organic sunscreens the same designation. This proposed rule by the FDA and our increasing understanding of multifactorial mechanisms of UVR damage are an impetus for innovation and advances in sun protective technology. A complete set of strategies designed to limit the risk of UV-induced skin cell malignant transformation and tumor development must address the fuller consideration of genetic, environmental, and immune factors that cooperatively drive cutaneous carcinogenesis. Recent advances in our understanding of the biochemical processes underpinning UVR associated cutaneous cellular damage, genotoxicity, and clonal expansion provide investigators with a spectrum of opportunities for technologic innovation in the prevention of skin cancer. Strategies to improve upon current topical sunscreen formulations have strived for broader UVR spectral coverage, more favorable aesthetics, increased adherence, and minimal penetration into the living epidermis. In addition to improved sunscreens, future topical therapies may target processes within the epidermis that contribute to carcinogenesis. These include reactive species quenching, delivery of DNA repair enzymes, and targeting of cytokines essential to the proliferation of mutant keratinocytes.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Sunscreen; photobiology; skin cancer; ultraviolet radiation
- PMID:
- 32226337
16.
Yale J Biol Med. 2020 Mar 27;93(1):49-54. eCollection 2020 Mar.
Probable African Tick Bite Fever in the United States.
Abstract
African tick bite fever (ATBF) is a tick-borne rickettsial disease most often observed in North American and European tourists returning home from the southern portion of Africa. Ticks infected with Rickettsia africae transmit this parasitic bacterium to humans, who subsequently develop an influenza-like illness, one or more inoculation eschars, and in some cases, a cutaneous rash. Because ATBF often presents with non-specific symptoms that suggest other infectious diseases, establishing the diagnosis may be difficult. Confirmatory assays, including serology and nucleic acid amplification, may take weeks to return and cannot help with acute treatment decisions. We present a case of a previously healthy 60-year-old woman who developed an illness strongly suggestive of ATBF after a missionary trip to Zimbabwe and discuss the disease's diagnostic challenges. Our paper also reviews the epidemiology of this disease and the currently available diagnostic laboratory tests and recommended treatment options.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
African tick bite fever; Ambylomma hebraeum; Rickettsia africae; Zimbabwe; eschar; rickettsia; spotted fever group rickettsia; tick-borne rickettsial disease; travel medicine; tropical medicine
- PMID:
- 32226336
17.
Yale J Biol Med. 2020 Mar 27;93(1):45-47. eCollection 2020 Mar.
Diltiazem-associated Photodistributed Hyperpigmentation.
Abstract
Diltiazem is a calcium-channel blocker commonly used for the treatment of hypertension. Common adverse effects include dizziness, headache, and edema. Fewer than 20 cases of diltiazem-associated photodistributed hyperpigmentation have been reported in the literature. Here, we present the case of a 71-year-old woman with new-onset facial hyperpigmentation 6 months after initiating treatment with diltiazem.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Diltiazem; hyperpigmentation; interface; photodistributed
- PMID:
- 32226335
18.
Yale J Biol Med. 2020 Mar 27;93(1):41-44. eCollection 2020 Mar.
Low-Dose Intralesional Recombinant Interferon-α2b in the Treatment of Mycosis Fungoides.
Abstract
Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is characterized by malignant CD4+ skin-homing T-cells that drive formation of cutaneous patches, plaques, and/or tumors. MF's known immunogenicity makes it an ideal candidate for local immunotherapy. Recombinant human leukocyte interferon-α2 (rIFN-α2) has well-established immunomodulatory, antiproliferative, and antitumor effects; and relatively low levels of endogenous IFN-α have been observed within MF lesions. As a systemic therapy delivered via subcutaneous (SC) or intramuscular (IM) injection, rIFN-α2 has previously shown efficacy against MF. Due to high levels of toxicity associated with the systemic dosing required for improvement of disease, rIFN-α2 has had limited use in the treatment of MF. For these reasons, we sought to deliver rIFN-2 as a local immunotherapy, and herein describe two cases of MF successfully managed with intralesional injections of low-dose rIFN-α2. With limited reporting in the medical literature, intralesional injection of rIFN-α2 has shown efficacy, but with high frequency of associated systemic side effects. Towards a better tolerated, localized immunotherapy, we initiated treatment in two MF patients with low dose (0.5 MU) rIFN-α2 per injection that led to marked responses, and subsequent dosing to 1.0 MU ultimately led to complete resolution of the treated lesions without the generalized side effects observed with systemic administration of rIFN-α2. These cases suggest that low-dose intralesional rIFN-α2 may be an efficacious and well-tolerated local immunotherapy for early stage MF, providing a therapeutic option for the management of chronic, recalcitrant lesions.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
cutaneous t-cell lymphoma (CTCL); intralesional; local immunotherapy; mycosis fungoides (MF); recombinant interferon-α2
- PMID:
- 32226334
19.
Yale J Biol Med. 2020 Mar 27;93(1):35-40. eCollection 2020 Mar.
Intravascular Large B-Cell Lymphoma: Clinical and Histopathologic Findings.
Abstract
Intravascular large B-cell lymphoma (IVLBCL) is a rare subset of extranodal non-Hodgkin lymphoma characterized by neoplastic lymphocytes within the lumina of small to medium-sized blood vessels. IVLBCLs are B-cell tumors that can present in essentially any organ system, including the skin. Cutaneous manifestations vary greatly and can mimic other skin disease which may delay diagnosis; in the absence of skin lesions, blind skin biopsies can be utilized for diagnosis. Early studies suggested that IVLBCL is a very aggressive lymphoma with high overall mortality rate and short survival times. However, earlier diagnosis and use of new treatment modalities have shown promise in recent studies. This case series illustrates the heterogeneity of clinical and pathologic presentations of this uncommon lymphoma.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
IVLBCL; classical variant; cutaneous variant; diffuse large b-cell lymphoma; intravascular large b-cell lymphoma
- PMID:
- 32226333
20.
Yale J Biol Med. 2020 Mar 27;93(1):29-34. eCollection 2020 Mar.
In vitro Reducing Effect of Cloxacillin on Minimum Inhibitory Concentrations to Imipenem, Meropenem, Ceftazidime, and Cefepime in Carbapenem-resistant Pseudomonas aeruginosa Isolates.
Abstract
Today, resistance to antibacterial agents is the most important problem facing public health. Pseudomonas aeruginosa is a common gram-negative bacterium and an important cause of nosocomial infections. Resistance to many antibiotics in strains of P. aeruginosa isolated from hospital settings such as cephalosporins and carbapenems have been recently reported. Therefore, the introduction of a new strategy to treat the infection of these organisms will be beneficial. In this study we determined the ability of cloxacillin to reduce Minimum Inhibitory Concentrations (MICs) of carbapenem-resistant P. aeruginosa to imipenem (IMI), meropenem (MEM), ceftazidime (CAZ), and cefepime (FEP). From 2015 to 2017, 61 non-duplicates of carbapenem-resistant P. aeruginosa were collected from clinical samples of hospitalized patients in Kerman, Iran. The MICs of the isolates to IMI, MEM, CAZ, and FEP with/without cloxacillin were determined by microbroth dilution method. The level of MIC of isolates to carbapenems (IMI and MEM) and cephalosporins (CAZ and FEP) ranged from 1-256 μg/mL and 4-1024 μg/mL alone and from 1-32 μg/mL and 1-512 μg/mL in combination with cloxacillin, respectively. The MIC showed a significant difference reduction after the addition of cloxacillin (P ≤ 0.05). Our results showed in vitro potentially of cloxacillin in reduction of MIC to IMI, MEM, CAZ, and FEP in multi-drug resistant P. aeruginosa, therefore combination of these antibiotics with cloxacillin could be beneficial for treatment of infections caused by multi-drug resistant P. aeruginosa.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Carbapenem-Resistance; Cloxacillin; Minimum Inhibitory Concentration; P. aeruginosa
- PMID:
- 32226332
21.
Yale J Biol Med. 2020 Mar 27;93(1):19-27. eCollection 2020 Mar.
Structural Basis for How Biologic Medicines Bind their Targets in Psoriasis Therapy.
Abstract
As biologic therapies become first line treatments for many inflammatory disorders, it becomes increasingly important for the practicing physician to be familiar with how these drugs function at the molecular level. This information is useful in making therapeutic decisions and helping patients understand their treatment options. It is critical to patient safety and clinical response that the molecular differences between these drugs inform prescribing practices. To this end, we present and analyze the available structural biology information about the biologics used in the treatment of psoriasis including inhibitors of tumor necrosis factor alpha (TNFα), interleukin-17 (IL-17), and interleukin-23 (IL-23). We describe and analyze the molecular surface character of known binding epitopes for medications in these classes, showing that significant differences exist in epitope location, hydrophobicity, and charge. Some of these differences can be correlated with clinical data, but our analysis ultimately points to the need for more structural information to allow for a better understanding of the structure-function relationship of biologic therapies.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
Biologics; IL-17; IL-23; TNF; drug binding; psoriasis; structural biology
- PMID:
- 32226331
22.
Yale J Biol Med. 2020 Mar 27;93(1):3-17. eCollection 2020 Mar.
Crystal Structure of Keratin 1/10(C401A) 2B Heterodimer Demonstrates a Proclivity for the C-Terminus of Helix 2B to Form Higher Order Molecular Contacts.
Abstract
We previously determined the crystal structure of the wild-type keratin 1/10 helix 2B heterodimer at 3.3 Å resolution. We proposed that the resolution of the diffraction data was limited due to the crystal packing effect from keratin 10 (K10) residue Cys401. Cys401K10 formed a disulfide-linkage with Cys401 from another K1/10 heterodimer, creating an "X-shaped" structure and a loose crystal packing arrangement. We hypothesized that mutation of Cys401K10 to alanine would eliminate the disulfide-linkage and improve crystal packing thereby increasing resolution of diffraction and enabling a more accurate side chain electron density map. Indeed, when a K10 Cys401Ala 2B mutant was paired with its native keratin 1 (K1) 2B heterodimer partner its x-ray crystal structure was determined at 2.07 Å resolution; the structure does not contain a disulfide linkage. Superposition of the K1/K10(Cys401Ala) 2B structure onto the wild-type K1/10 2B heterodimer structure had a root-mean-square-deviation of 1.88 Å; the variability in the atomic positions reflects the dynamic motion expected in this filamentous coiled-coil complex. The electrostatic, hydrophobic, and contour features of the molecular surface are similar to the lower resolution wild-type structure. We postulated that elimination of the disulfide linkage in the K1/K10(Cys401Ala) 2B structure could allow for the 2B heterodimers to bind/pack in the A22 tetramer configuration associated with mature keratin intermediate filament assembly. Analysis of the crystal packing revealed a half-staggered anti-parallel tetrameric complex of 2B heterodimers; however, their register is not consistent with models of the A22 mode of tetrameric alignment or prior biochemical cross-linking studies.
Copyright ©2020, Yale Journal of Biology and Medicine.
KEYWORDS:
assembly; disulfide bond; heterodimer; intermediate filament; keratin; structure
- PMID:
- 32226330
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