Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.

Concomitant EGFR Mutations and ALK Rearrangements in Lung Adenocarcinoma Treated With Osimertinib.

Lung cancer is the third most common cancer in addition to being the cancer responsible for the most annual deaths in the United States, comprising 15% of all diagnosed cancers, and 28% of all cancer deaths in 2020. Major advances in survival are because of gene sequencing and the advent of targeted biological therapy. The prevalence of epidermal growth factor receptor (EGFR) mutations coexisting with anaplastic lymphoma kinase (ALK) rearrangements is quite low. However, the clinical relevance and effective treatment of these cancers require further investigation. This case series describes two patients diagnosed with stage IV adenocarcinoma with coexisting EGFR and ALK rearrangements. In Case 1, a 73-year-old male presented with worsening ataxia and headaches. In Case 2, a 64-year-old female presented with worsening dyspnea. Molecular studies revealed ALK gene fusion and the L861Q EGFR mutation in Case 1 and L858R EGFR mutation and ALK gene fusion in Case 2. Both patients received a gamma knife and an EGFR-tyrosine kinase inhibitor (TKI), osimertinib. In one of the cases, following the discovery of new brain metastases, the dose of osimertinib was increased from 80 to 160 mg. The patient passed away nine months after beginning EGFR-TKI treatment, one month after increasing the dose. The second patient experienced a significant interval reduction in the size of enhancing metastasis in both the right frontal and left parietal lobe after four months of EGFR-TKI treatment. The cases of coexisting EGFR mutations and ALK rearrangements are quite rare, and treatment can be challenging. Here, EGFR-TKI had a mixed response among our patients.

Cutaneous tuberculosis in the pediatric population: A review.

Importance: Tuberculosis (TB) is a significant health concern, affecting over 1.5 million people annually worldwide, with the incidence increasing in the United States from 2020 to 2021. The pediatric population is particularly vulnerable to TB. Extrapulmonary manifestations of TB include cutaneous tuberculosis (CTB). Observations: There are 8 forms of CTB. Lupus vulgaris (LV) is the second most common form of pediatric CTB which presents nontender plaques or nodules with ulceration that progress to well-defined, scaly plaques. Tuberculous chancre results from exogenous inoculation and lesions contain large amounts of acid-fast bacilli (AFB). Clinically, tuberculous chancre presents as erythematous papules which form firm nontender ulcers. Tuberculosis verrucose cutis (TVC) presents as small papules surrounded by inflammation that develops into a wart-like lesion. Periorificial lesions are rare and present as painful ulcers in the oral or perineal regions. Scrofuloderma is the most common form of pediatric CTB and presents as nodules that ulcerate, forming purulent sinus tracts. Tuberculosis miliaris cutis disseminate presents as widespread papules and crusted vesicles. Metastatic abscesses present as multiple nodules that may ulcerate or form draining sinus tracts. Lastly, tuberculid forms include lichen scrofulosorum (LS), which presents as lichenoid papules which may form plaques and scale, and papulonecrotic tuberculid, which presents as necrotic papules. All forms of cutaneous tuberculosis can be treated with the standard 6-month, four-drug anti-tuberculosis treatment (ATT). Some cases of CTB may require debriding and surgical management in addition to ATT. Conclusions and Relevance: Determining the type of CTB can be challenging clinically. Histopathology is needed to make the diagnosis. Chest x-ray and a review of systems should be obtained for CTB patients to determine if there are other extrapulmonary manifestations of TB. All types are treated with 6 months of ATT.