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1.
J Drugs Dermatol ; 23(6): e144-e148, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38834228

ABSTRACT

Bullous pemphigoid is often difficult to treat with the limited therapies available. Here, we describe clinical outcomes among 30 adults with bullous pemphigoid patients treated with dupilumab. We performed a multicenter, retrospective case series between March 2020 to August 2022. Patients received a loading dose of dupilumab 600 mg, followed by 300 mg maintenance dose with varying administration frequency tailored to individual patient response. All patients experienced at least some improvement in blister formation and pruritus, with 23 (76.7%) of patients demonstrating either complete clearance of blistering or marked response. Complete clearance of pruritus or marked response was noted in 25 (83.3%) of patients. Eight patients were effectively maintained solely on dupilumab. One (3.3%) patient reported an injection site reaction. Thirty patients represent a small sample, however, to our knowledge, this is the second largest group of BP treated with dupilumab. Furthermore, we provide an understandable framework for clinicians outside of academics to follow and assess treatment responses in their BP patients treated with dupilumab. Dupilumab should be considered as a therapeutic option in patients with bullous pemphigoid given its ability to induce sustained blistering and pruritus response in both typical and refractory cases while maintaining a favorable safety profile. J Drugs Dermatol. 2024;23(6):e144-e148. doi:10.36849/JDD.8258e.


Subject(s)
Antibodies, Monoclonal, Humanized , Pemphigoid, Bullous , Pruritus , Humans , Pemphigoid, Bullous/drug therapy , Pemphigoid, Bullous/diagnosis , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Retrospective Studies , Female , Male , Aged , Middle Aged , Treatment Outcome , Aged, 80 and over , Pruritus/drug therapy , Pruritus/etiology , Pruritus/diagnosis , Adult , Injection Site Reaction/etiology , Injection Site Reaction/diagnosis
2.
J Phys Chem B ; 128(20): 5044-5054, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38727627

ABSTRACT

In this work, the vapor-liquid-liquid equilibrium (VLLE) of the water/n-pentane, water/n-hexane, water/n-octane, and water/n-decane binary systems is calculated by computer simulation using the NVT-Gibbs ensemble (in the version of three simulation boxes) combined with the configurational bias Monte Carlo method. The combination of both methods, the molecular potential models used, and the simulation details allowed us to calculate the triphasic equilibrium properties of the systems studied: the densities of the three phases in equilibrium, their compositions, and potential energies. In previous works, these simulations were not carried out at a temperature range nor water/n-alkanes systems simulated in this work, probably because they are highly nonideal systems; so, to the best of our knowledge, this is the first time that this phenomenon is studied in detail. The results from VLLE simulations of the water/n-pentane system for temperatures from 343.2 to 435 K, the water/n-hexane system for temperatures from 373.11 to 473.15 K, the water/n-octane system for temperatures from 310.9 to 500 K, and for the water/n-decane system for temperatures from 374.15 to 525 K are reported here. The temperature range was selected in concordance with the experimental data available for an adequate study of the VLLE simulation results. The subcritical densities (vapor and liquid rich in n-alkane phases) at various temperatures fit well with the scaling law and the law of rectilinear diameters, allowing the estimation of upper critical end point temperature and density of the VLLE. The simulation results show a good prediction with experimental data reports in the literature.

3.
Front Oncol ; 14: 1341766, 2024.
Article in English | MEDLINE | ID: mdl-38571493

ABSTRACT

Introduction: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4BG13D and its membrane transporter (PDE6δ). Methods: The antitumor potential of C14 and P8 was assessed using TNBC cell lines, MDA-MB-231, and the radioresistant derivative MDA-MB-231RR, both carrying the K-Ras4B> G13D mutation. We investigated the compounds' effects on K-Ras signaling pathways, cell viability, and tumor growth in vivo. Results: Western blotting analysis determined the negative impact of C14 and P8 on the activation of mutant K-Ras signaling pathways in MDA-MB-231 and MDA-MB-231RR cells. Proliferation assays demonstrated their efficacy as cytotoxic agents against K-RasG13D mutant cancer cells and in inducing apoptosis. Clonogenic assays proven their ability to inhibit TNBC and radioresistant TNBC cell clonogenicity. In In vivo studies, C14 and P8 inhibited tumor growth and reduced proliferation, angiogenesis, and cell cycle progression markers. Discussion: These findings suggest that C14 and P8 could serve as promising adjuvant treatments for TNBC, particularly for non-responders to standard therapies. By targeting overactivated K-Ras and its membrane transporter, these compounds offer potential therapeutic benefits against TNBC, including its radioresistant form. Further research and clinical trials are warranted to validate their efficacy and safety as novel TNBC treatments.

4.
Arch Dermatol Res ; 316(4): 103, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38485858

ABSTRACT

While time spent practicing inpatient dermatology has decreased since the 1990s, less is known about the current state of inpatient dermatology. We describe the distribution and frequency of inpatient dermatology encounters servicing the United States Medicare population between 2013 and 2019. Cross-sectional analysis of publicly available inpatient Medicare Part B claims data from 2013 to 2019 was conducted. Main outcomes and measures were characteristics and trends of dermatologists performing inpatient encounters. Categorical variables were compared using χ2 analysis. Trends were analyzed for linearity using Pearson correlation coefficient. 782 physicians met inclusion criteria for inclusion. Dermatologists were more often male (56.5%), possessing allopathic Medical Doctorate (MD) (86.3%), and in metropolitan settings (98.2%). However, proportion of female inpatient dermatologists increased significantly (37.9% to 46.2%). Across rural and metropolitan practices, number of inpatient physicians (2013: 356; 2019: 281) and number of medical centers in which dermatology encounters occurred (2013: 239; 2019: 157) decreased, more significantly in non-residency-associated institutions. Spatial analysis revealed wide regions lacking dermatologists meeting defined criteria. Limitations included the need for ten Medicare inpatient encounters for inclusion, counties without reported data. In conclusion, the number of dermatologists performing > 10 inpatient encounters per year is decreasing, and large variations exist in the number of U.S. inpatient dermatology visits.


Subject(s)
Dermatology , Aged , Humans , Male , Female , United States , Medicare , Cross-Sectional Studies , Inpatients , Workforce
6.
Int J Mol Sci ; 25(2)2024 Jan 12.
Article in English | MEDLINE | ID: mdl-38256028

ABSTRACT

Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, 30-fold more frequent than in public databases. We thus characterized the biophysical phenotypes of wildtype and mutant IKs co-expressing these alleles with the ß-subunit minK in HEK293 cells. KCNQ1 p.446E homozygosity significantly shifted IKs voltage dependence to hyperpolarizing potentials in basal conditions (gain of function) but failed to shift voltage dependence to hyperpolarizing potentials (loss of function) in the presence of 8Br-cAMP, a protein kinase A activator. Basal IKs activation kinetics did not differ among genotypes, but in response to 8Br-cAMP, IKs 446 E/E (homozygous) activation kinetics were slower at the most positive potentials. Protein modeling predicted a slower transition of the 446E Kv7.1 tetrameric channel to the stabilized open state. In conclusion, biophysical and modelling evidence shows that the KCNQ1 p.D446E variant has complex functional consequences including both gain and loss of function, suggesting a contribution to the pathogenesis of arrhythmogenic phenotypes as a functional risk allele.


Subject(s)
Arrhythmias, Cardiac , Channelopathies , KCNQ1 Potassium Channel , Humans , Alleles , Arrhythmias, Cardiac/genetics , Cyclic AMP-Dependent Protein Kinases , HEK293 Cells , KCNQ1 Potassium Channel/genetics , Phenotype
8.
Colorectal Dis ; 25(7): 1506-1511, 2023 07.
Article in English | MEDLINE | ID: mdl-37874041

ABSTRACT

AIM: Perioperative bladder catheterization is a controversial issue. Most current recommendations are based on data from open surgery extrapolated to enhanced recovery after surgery or fast-track programmes ranging between 24 and 48 h. The aim of this study is to provide a rationale for reducing catheterization time while at the same time avoiding acute urine retention (AUR), in patients undergoing scheduled laparoscopic colon surgery. METHOD: This is a multicentre, prospective, controlled, randomized non-inferiority study of bladder catheter management in patients undergoing scheduled laparoscopic colon surgery, randomized into two groups: experimental (with catheter removal immediately after surgery) and control (with catheter removal 24 h post-surgery). The main outcome will be the development of AUR, and secondary outcomes the development of urinary infection within the first 30 days and hospital stay. Demographic, surgical and pathological variables will also be evaluated, especially the development of adverse effects assessed according to the Clavien scale and the Comprehensive Complication Index. Following the literature, we assume an incidence of AUR of 11% and a margin of non-inferiority (delta) of 8% and estimate that a sample size of 208 patients per group will be required (with an estimated 10% of losses per group). CONCLUSIONS: In this study we try to demonstrate that the bladder catheter can be removed immediately after scheduled laparoscopic colon surgery, without increasing acute urine retention. This measure would offers the benefits of earlier mobilization and reduces catheter-related morbidity.


Subject(s)
Urinary Bladder , Urinary Retention , Humans , Urinary Bladder/surgery , Prospective Studies , Urinary Catheterization/adverse effects , Urinary Retention/etiology , Urinary Catheters/adverse effects , Colon/surgery
9.
Front Med (Lausanne) ; 10: 1213889, 2023.
Article in English | MEDLINE | ID: mdl-37901413

ABSTRACT

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

10.
Life Sci Alliance ; 6(12)2023 12.
Article in English | MEDLINE | ID: mdl-37813486

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.


Subject(s)
Antineoplastic Agents , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Mice , Animals , Cell Line, Tumor , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Antineoplastic Agents/pharmacology , Pancreatic Neoplasms
11.
JAAD Int ; 12: 112-120, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37409319

ABSTRACT

Background: Teledermatology (TD) is an important method for increasing access to care in outpatient settings. However, less is known regarding its use in emergency/urgent care centers. Objective: To evaluate the effect of TD on urgent care emergency center (UCEC) dwell time and postencounter utilization. Study type and methods: This retrospective cohort study evaluated patients in a safety-net hospital (Parkland Health, Dallas, Texas, USA) UCEC, who (1) received a TD consult in 2018, (2) were referred to dermatology clinic in 2017, or (3) were referred to dermatology clinic in 2018 without a TD consult. Results: We evaluated 2024 patients from 2017 to 2018. Of the 973 referred to dermatology clinic in 2018, 332 (34%) received TD consultations. Mean dwell time for patients receiving TD was longer versus the 2017 cohort (303 vs 204 minutes, respectively). Patients receiving TD consultation with inflammatory skin conditions had lower odds of dermatology clinic visits compared with those that did not (odds ratio, 0.5; 95% CI, 0.3-0.8). Teledermatology was not associated with differences in repeat UCEC utilization. Limitations: Single institution study and inability to account for differences in patient complexity. Conclusion: TD increases dwell time in a safety-net hospital's UCEC but can reduce dermatology clinic utilization for patients with inflammatory skin conditions.

13.
HIV Med ; 24(10): 1056-1065, 2023 10.
Article in English | MEDLINE | ID: mdl-37336551

ABSTRACT

INTRODUCTION: Compared with previous geographically localized outbreaks of monkeypox (MPOX), the scale of the 2022 global mpox outbreak has been unprecedented, yet the clinical features of this outbreak remain incompletely characterized. METHODS: We identified patients diagnosed with mpox by polymerase chain reaction (PCR; n = 36) from July to September 2022 at a single, tertiary care institution in the USA. Demographics, clinical presentation, infection course, and histopathologic features were reviewed. RESULTS AND CONCLUSION: Men who have sex with men (89%) and people living with HIV (97%) were disproportionately affected. While fever and chills (56%) were common, some patients (23%) denied any prodromal symptoms. Skin lesions showed a wide range of morphologies, including papules and pustules, and lesions showed localized, not generalized, spread. Erythema was also less appreciable in skin of colour patients (74%). Atypical clinical features and intercurrent skin diseases masked the clinical recognition of several cases, which were ultimately diagnosed by PCR. Biopsies showed viral cytopathic changes consistent with Orthopoxvirus infections. All patients in this case series recovered without complications, although six patients (17%) with severe symptoms were treated with tecovirimat without complication.


Subject(s)
HIV Infections , Mpox (monkeypox) , Sexual and Gender Minorities , Humans , Male , Disease Outbreaks , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Homosexuality, Male , Mpox (monkeypox)/epidemiology
15.
JAMA Dermatol ; 159(7): 772-777, 2023 07 01.
Article in English | MEDLINE | ID: mdl-37256599

ABSTRACT

Importance: Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives: To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review: A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings: In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance: This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.


Subject(s)
Stevens-Johnson Syndrome , Humans , Stevens-Johnson Syndrome/diagnosis , Consensus , Delphi Technique , Skin/pathology , Head , Blister/pathology
18.
Clin Infect Dis ; 76(10): 1843-1846, 2023 May 24.
Article in English | MEDLINE | ID: mdl-36718662

ABSTRACT

In the current mpox outbreak, infections are usually self-limited. We describe 3 patients with uncontrolled HIV and mpox infections lasting months, causing debilitating lesions, complications, and death, despite initiating anti-mpox and antiretroviral therapy. Delayed treatment of mpox with antiviral agents may contribute to poor outcomes in severely immunocompromised patients.


Subject(s)
HIV Infections , HIV , Mpox (monkeypox) , Humans , Antiviral Agents/therapeutic use , Disease Outbreaks , HIV Infections/complications , HIV Infections/drug therapy , Mpox (monkeypox)/complications
19.
JAMA Dermatol ; 159(3): 332, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36652219

ABSTRACT

This case report describes a large, purpuric plaque involving most of the right face with associated periorbital swelling but without ulceration.


Subject(s)
Hemangiosarcoma , Skin Neoplasms , Humans , Hemangiosarcoma/diagnosis , Skin Neoplasms/diagnosis , Diagnosis, Differential
20.
J Biomol Struct Dyn ; 41(2): 423-434, 2023 02.
Article in English | MEDLINE | ID: mdl-34821199

ABSTRACT

The amyloid fibres have been related to many diseases. The molten globule intermediate has been proposed to form part of the folding pathway of many proteins. In the present study, we investigated the mechanism of amyloid-fibres formation of hen egg-white lysozyme (HEWL) incubated in a potassium phosphate buffer, pH 11.8, 100 mM, at 37 °C for 30 h, and evaluated the influence of Cu(II) present in two salts (CuSO4 and CuCl2) during fibrillogenesis. Co-incubation and post-incubation of lysozyme with copper salts reduced the fluorescence signal of thioflavin T with an increment in the intrinsic fluorescence of the protein. The ANS fluorescence test showed that incubation of HEWL for 6 h generated a molten globule intermediate state that formed amyloid fibres when incubation was carried out for a 30-h timespan. Dynamic light scattering showed a heterogeneous population of states in samples incubated in the absence or the presence of salts during the fibrillation process. The existence of a reducing potential was verified during the formation of HEWL amyloid fibres with the bathocuproine disulphonate test. Transmission electron microscopy confirmed the presence and absence of fibres in solutions incubated with and without Cu(II). This work demonstrated that lysozyme formed amyloid fibres at 37 °C and copper inhibited its formation.Communicated by Ramaswamy H. Sarma.


Subject(s)
Muramidase , Salts , Salts/pharmacology , Muramidase/metabolism , Copper , Dynamic Light Scattering , Amyloid
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