Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

Loss of polarity regulators initiates gasdermin-E-mediated pyroptosis in syncytiotrophoblasts.

The syncytiotrophoblast is a human epithelial cell that is bathed in maternal blood on the maternal-facing surface of the human placenta. It therefore acts as a barrier and exchange interface between the mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblasts display a loss of microvilli, which is a marker of aberrant apical-basal polarization, but little data exist about the regulation of syncytiotrophoblast polarity. Atypical PKC isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin-E-dependent pyroptosis, a form of programmed necrosis. We also establish that TNF-α induces an isoform-specific decrease in aPKC expression and gasdermin-E-dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of the syncytiotrophoblast function and a pathogenically relevant pro-inflammatory cytokine leads to the induction of programmed necrosis at the maternal-fetal interface. Hence, our results have important implications for the pathobiology of placental disorders like preeclampsia.

The Elusive Sarcoidosis, an Eight-Year Journey to the Diagnosis of Sarcoidosis: A Case Report.

We present a unique case of a patient coming to our internal medicine clinic with intermittent diffuse lymphadenopathy and non-specific symptoms for the past eight years. Initially, the patient was thought to have carcinoma of unknown primary origin, given the abnormalities seen in her imaging. The diagnosis of sarcoidosis was also dismissed, given that the patient had not responded to steroids with negative laboratory support. The patient was referred to several specialists, and only after a pulmonary biopsy was a non-caseating granuloma revealed after multiple prior failed biopsies. The patient was placed on infusion therapy and responded positively. This case demonstrates a challenging diagnosis and treatment which emphasizes the importance of considering alternative treatments if the initial therapy fails.

7-Ketocholesterol Promotes Retinal Pigment Epithelium Senescence and Fibrosis of Choroidal Neovascularization via IQGAP1 Phosphorylation-Dependent Signaling.

Accumulation of 7-ketocholesterol (7KC) occurs in age-related macular degeneration (AMD) and was found previously to promote fibrosis, an untreatable cause of vision loss, partly through induction of endothelial-mesenchymal transition. To address the hypothesis that 7KC causes mesenchymal transition of retinal pigment epithelial cells (RPE), we exposed human primary RPE (hRPE) to 7KC or a control. 7KC-treated hRPE did not manifest increased mesenchymal markers, but instead maintained RPE-specific proteins and exhibited signs of senescence with increased serine phosphorylation of histone H3, serine/threonine phosphorylation of mammalian target of rapamycin (p-mTOR), p16 and p21, ß-galactosidase labeling, and reduced LaminB1, suggesting senescence. The cells also developed senescence-associated secretory phenotype (SASP) determined by increased IL-1ß, IL-6, and VEGF through mTOR-mediated NF-κB signaling, and reduced barrier integrity that was restored by the mTOR inhibitor, rapamycin. 7KC-induced p21, VEGF, and IL-1ß were inhibited by an inhibitor of protein kinase C. The kinase regulates IQGAP1 serine phosphorylation. Furthermore, after 7KC injection and laser-induced injury, mice with an IQGAP1 serine 1441-point mutation had significantly reduced fibrosis compared to littermate control mice. Our results provide evidence that age-related accumulation of 7KC in drusen mediates senescence and SASP in RPE, and IQGAP1 serine phosphorylation is important in causing fibrosis in AMD.

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis.

INTRODUCTION: Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP). CASE REPORT: We report an unusual case of pneumonitis with atypical imaging in a patient who received pembrolizumab for metastatic p16-positive squamous cell carcinoma of the base of the tongue. We discuss the approach to the recognition and management of atypical CIP in patients on pembrolizumab with the intent to standardize workup and increase awareness among healthcare providers in the new era of immunotherapy. MANAGEMENT AND OUTCOME: Serologic workup including laboratory studies for complete blood count (CBC), lactate, procalcitonin, SARS-CoV-2 (COVID-19), Legionella, Cytomegalovirus (CMV), Coccidioides, Coxiella, and viral respiratory panel were negative for infectious processes. Since CIP was suspected, the patient was started on steroid therapy. Interval computed tomography (CT) of the chest without contrast showed a resolution of pneumonitis. DISCUSSION: In this case report, we discuss our workup of CIP and initial testing to rule out other possible causes of the patient's symptoms and radiographic findings, and management of the patient's diagnosis of atypical CIP which led to complete clinical recovery from CIP.

Examining the context, logistics, and outcomes of food prescription programs: A scoping review.

BACKGROUND: Obesity and associated metabolic conditions are endemic. Finding new strategies to mitigate the impact on wellbeing and healthcare systems is critical. Food prescription programs (FPPs) have been promoted as one route to address this problem in a way that simultaneously addresses the socio-cultural context of obesity. Yet, little is known about the standard practices and logistics of using food prescription programs as an effective intervention. OBJECTIVES: To 1) identify the context in which food prescription programs are used; 2) identify implementation logistics of food prescription program; and 3) understand the scope of food prescription program outcomes. METHODS: A scoping review was conducted from October 2019 to May 2020 using Google Scholar, EBSCOhost, and AcademicOne Search to identify research articles focused on the implementation of prescription food programs in the US. Updates to articles were made in May of 2021 and May of 2022 to ensure the most up-to-date sample for analysis. There was no publication date restriction for article inclusion. RESULTS: A total of 213 articles were identified for abstract review via the search strategy, and 30 articles were included for analysis following article exclusion. Overall, there was little consistency among included articles regarding the target population, participant recruitment, delivery, and evaluation of the food prescription programs implemented. Most food prescription programs studied were associated with farmers markets, lasted less than 6 months, and utilized produce consumption and biometric data as primary outcomes measures. CONCLUSION: Significant gaps in the literature concerning the long-term effectiveness, impact on health behaviors, screening of eligible participants, and logistics for implementation were identified. Future research should focus on addressing these shortcomings in the current literature to improve the implementation, sustainability, and scaling of food prescription programs.

Surgically Enucleated Gastrointestinal Tumor of the Rectovaginal Septum.

The rectovaginal septum is a rare location for gastrointestinal stromal tumors (GIST) to occur. When such is the case, the question arises as to whether the lesion, which is morphologically and immunophenotypically identical to its gastrointestinal counterpart, should be referred to as an extragastrointestinal stromal tumor (EGIST). A 77-year-old, gravida 4, para 4004 post-menopausal female with an unremarkable gynecologic history presented with brown vaginal discharge. On examination, a 4 to 5-cm nodule was palpated along the rectovaginal septum. Ultrasound revealed a 4.8-cm circumscribed, solid mass with internal blood flow located posterior and inferior to the cervix. At laparoscopy, the uterus and adnexae were deemed to be normal for age, without gross pathologic abnormalities. The nodule was resected in an enucleation procedure; subsequent histopathologic examination revealed a low-grade, spindled cell neoplasm with diffuse immunoreactivity for CD117 (cKit) and DOG1, diagnostic of GIST. Further molecular testing elucidated a mutation in exon 9 of the Kit gene. A decision was made by the patient for close observation; there is no clinical or radiographic evidence of recurrence one year after initial diagnosis.

Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1.

We identified a lead series of p38 mitogen-activated protein kinase inhibitors using a structure-based design strategy from high-throughput screening of hit compound 1. X-ray crystallography of 1 with the kinase showed an infrequent flip of the peptide bond between Met109 and Gly110, which was considered to lead to high kinase selectivity. Our structure-based design strategy was to conduct scaffold transformation of 1 with maintenance of hydrogen bond interactions with the flipped hinge backbone of the enzyme. In accordance with this strategy, we focused on scaffold transformation to identify imidazo[4,5-b]pyridin-2-one derivatives as potent inhibitors of the p38 MAP kinase. Of the compounds evaluated, 21 was found to be a potent inhibitor of the p38 MAP kinase, lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production in human monocytic leukemia cells, and TNF-α-induced production of interleukin-8 in human whole blood cells. Herein we describe the discovery of potent and orally bioavailable imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors that suppressed cytokine production in a human whole blood cell-based assay.

A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens.

American trypanosomiasis, commonly known as Chagas disease, is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. The chronic form of the infection often causes debilitating morbidity and mortality. However, the current treatment for the disease is typically inadequate owing to drug toxicity and poor efficacy, necessitating a continual effort to discover and develop new antiparasitic therapeutic agents. The structure of T. cruzi histidyl-tRNA synthetase (HisRS), a validated drug target, has previously been reported. Based on this structure and those of human cytosolic HisRS, opportunities for the development of specific inhibitors were identified. Here, efforts are reported to identify small molecules that bind to T. cruzi HisRS through fragment-based crystallographic screening in order to arrive at chemical starting points for the development of specific inhibitors. T. cruzi HisRS was soaked into 68 different cocktails from the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library and diffraction data were collected to identify bound fragments after soaking. A total of 15 fragments were identified, all bound to the same site on the protein, revealing a fragment-binding hotspot adjacent to the ATP-binding pocket. On the basis of the initial hits, the design of reactive fragments targeting the hotspot which would be simultaneously covalently linked to a cysteine residue present only in trypanosomatid HisRS was initiated. Inhibition of T. cruzi HisRS was observed with the resultant reactive fragments and the anticipated binding mode was confirmed crystallographically. These results form a platform for the development of future generations of selective inhibitors for trypanosomatid HisRS.

EORTC QLQ-BR23 and FACT-B for the assessment of quality of life in patients with breast cancer: a literature review.

BACKGROUND: This study aims to compare the development, characteristics and validity of two widely used tools in the breast cancer population, the EORTC QLQ-BR23 and the FACT-B. METHODS: A literature search was conducted using Ovid MEDLINE, OLDMEDLINE, Embase, Embase Classic and the Cochrane Central Register of Controlled Trials to identify relevant studies. RESULTS: Both tools were found to be reliable and valid. The QLQ-BR23 focuses on physical function, whereas the FACT-B emphasizes emotional well-being. Scoring, item format, organization and response options differ between questionnaires. CONCLUSION: Overall, both questionnaires are effective in assessing breast cancer-specific quality of life. Clear similarities and differences between the two tools exist. Decision-making between the questionnaires should be based on the purpose and design of the study.

Development, characteristics and validity of the EORTC QLQ-PR25 and the FACT-P for assessment of quality of life in prostate cancer patients.

This review aims to compare and contrast the development, characteristics and validity of two widely used quality of life assessment tools in patients with prostate cancers: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) and Functional Assessment of Chronic Illness Therapy (FACT-P). Both questionnaires present several strengths as well as some limitations in measuring the quality of life of prostate cancer patients. Each tool may be selected accordingly based on study design and needs.

Radioembolization of the spleen: a revisited approach for the treatment of malignant lymphomatous splenomegaly.

Intraarterial administration of (90)Y microspheres to the spleen in patients with malignant lymphoma was mentioned once in the literature in 1973. This case study illustrates the potential indication of selective internal radiotherapy in a heavily pretreated patient with highly refractory disease with a marginal zone lymphoma in leukemic phase and symptomatic splenomegaly. We describe the clinical course of disease; the biological and clinical response to the treatment after radioembolization; and simulation and dosimetry by multimodal imaging via single-photon emission computed tomography and computed tomography. The advantages of radioembolization for the management of lymphomatous splenomegaly are discussed.

An Update on the Quality of Life Measurements in Lung Cancer Patients Receiving Palliative Radiotherapy: A Literature Review.

To conduct a systematic review on validated instruments used to assess quality of life (QOL) in patients with either primary or metastatic lung neoplasms. A literature search was conducted through the Embase (1950 - 2012 week 30) and Medline (1946 - 2012 week 3 July) databases. All compiled studies utilized QOL or symptom palliation as a primary or secondary outcome for patients with advanced lung cancer. A total of 17 studies met our criteria. Four questionnaires were most commonly used: the EORTC QLQ-C-30, the EORTC QLQ-LC-13, the Rotterdam Symptom Check-list (RSCL), and the Hospital Anxiety and Depression Scale (HADS). The limited number of studies assessing QOL in patients with advanced lung cancer suggests that QOL is still an uncommon endpoint for this patient population. Nine of seventeen (53%) studies evaluated QOL in their cohorts and out of those nine, seven (77%) included the use of a lung-specific tool. In total there were eleven of seventeen (65%) studies that evaluated symptom palliation, indicating the relevance of symptom palliation as an endpoint in this population. It is encouraged that lung specific QOL questionnaires, such as the FACT-L and the EORTC QLQ LC-13, be used in tandem with general questionnaires, such as the FACT-G and the EORTC QLQ C-30, in advanced lung cancer patients undergoing radiotherapy. Clinicians should also be advised to focus more on QOL assessment.