Engineered CD47 protects T cells for enhanced antitumour immunity.

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

New-onset seizures: an unusual neurologic manifestation of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory condition primarily affecting the musculoskeletal system but can often involve other organ systems as well. Rheumatoid meningitis is a rare central nervous system (CNS) manifestation of RA characterized by pachymeningeal and leptomeningeal enhancement. Herein, we present a case of a 64-year-old male who presented with left lower extremity weakness and witnessed seizures. The diagnostic work-up, including lumbar puncture, brain MRI and meningeal biopsy ruled out malignancy and were consistent with the diagnosis of rheumatoid meningitis. The patient was discharged on high-dose steroids along with anti-seizure medications. On subsequent follow-up visits, the patient remained seizure-free.

A Case of Concurrence of Clonorchis Sinensis and Pancreatic Adenocarcinoma-A Diagnostic Dilemma.

Clonorchis Sinensis, a common liver fluke, is known to cause biliary disease and can present with a wide array of symptoms. It's mostly found in Asian countries due to consumption of undercooked or raw fish. Although Cholangiocarcinoma is a known serious complication of this disease, Pancreatic neoplasms are rare and have seldom been reported. Here, we report a case of an 80-year-old man who presents with pancreatic adenocarcinoma associated with Clonorchis Sinensis infection.

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance.

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

Oestrogen And Progesterone Receptors' Expression Pattern In Fibro-Adenoma Of The Female Breast.

BACKGROUND: Fibro-adenoma is the most common benign condition of the female breast comprising about 68% of all breast lumps. Fibroadenoma is an independent risk factor for the development of breast cancer. Complex fibroadenoma has a 2-3-fold increased risk ratio and simple fibroadenoma has 1.49 times increased risk ratio of developing cancer than the normal population over a period of 20 years. This study aimed to qualitatively check the frequency of oestrogen receptor-positive and progesterone receptor-positive cases of fibroadenoma in our region. METHODS: This cross-sectional study was conducted in the pathology department of Ayub Medical College, Abbottabad from June 2020 to December 2021. Biopsy confirmed cases of fibroadenoma were examined using immune-histochemical stains to score qualitatively the expression pattern of ER and PR. Data was analyzed and assessed using SPSS version 25. A p-value of ≤0.05 was considered statistically significant. RESULTS: The mean age of patients who presented with fibro-adenoma was 24.5±9.29 years with a median age of 21.5 years. In most cases, oestrogen receptor expression was mild 23 (54.76%) whereas progesterone receptor expression was severe 19 (45.23%). On chi-square test, the pattern of progesterone receptor expression for the category of hormone intake showed significant differences. Whereas, the pattern of oestrogen receptor expression for the categories of marital status, history of hormone intake, history of menstrual cycle and type of fibroadenoma showed no statistically significant difference. CONCLUSIONS: Further study into the pathogenesis of fibroadenoma is required to understand the role of ER and PR and explore the therapeutic potential of such drugs that affects these receptors. Cabling.

Diagnosis of Adrenocortical Carcinoma with Hypercortisolism in a Patient Presenting with Hypokalemic Metabolic Alkalosis.

Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual incidence of 0.7-2 cases per million. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC are diagnosed incidentally. A careful history, physical exam, and pertinent lab investigations are necessary to reach the diagnosis. Surgical resection is the cornerstone of treatment in localized ACC; however, systemic chemotherapy with mitotane is preferred in patients with widespread disease or those who are not ideal candidates for surgery.

Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage.

BACKGROUND AND PURPOSE: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-ß, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. METHODS: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE-ε4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. RESULTS: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. CONCLUSIONS: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.

Rhabdomyosarcoma from uterus to heart.

Rhabdomyosarcoma (RMS) is a malignant soft tissue tumor of the pediatric population which is  rarely seen in adults. Metastatic rhabdomyosarcoma is even rarer. We present an unusual case of a 49 year old female presenting with palpitations and uterine bleeding. An Echo-cardiogram revealed a large oval mass on the posterior mitral leaflet and a Computerized Tomography (CT) scan of the abdomen revealed a uterine growth. Surgical excision of the cardiac mass was done and histological analysis of cardiac lesion confirmed it to be rhabdomyosarcoma with a primary source in the uterus. The patient became asymptomatic from a cardiac standpoint after excision of the mass and was scheduled for chemo/radiation therapy for the primary uterine malignancy. Metastatic cardiac rhabdomyosarcoma can be confused with a myxoma or any other primary or secondary cardiac tumors resulting in delayed diagnosis. However, its aggressive nature makes it a life-threatening tumor that requires an early diagnosis to prevent fatal consequences.

Expression-Based Cell Lineage Analysis in Drosophila Through a Course-Based Research Experience for Early Undergraduates.

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.

The translation of non-canonical open reading frames controls mucosal immunity.

The annotation of the mammalian protein-coding genome is incomplete. Arbitrary size restriction of open reading frames (ORFs) and the absolute requirement for a methionine codon as the sole initiator of translation have constrained the identification of potentially important transcripts with non-canonical protein-coding potential1,2. Here, using unbiased transcriptomic approaches in macrophages that respond to bacterial infection, we show that ribosomes associate with a large number of RNAs that were previously annotated as 'non-protein coding'. Although the idea that such non-canonical ORFs can encode functional proteins is controversial3,4, we identify a range of short and non-ATG-initiated ORFs that can generate stable and spatially distinct proteins. Notably, we show that the translation of a new ORF 'hidden' within the long non-coding RNA Aw112010 is essential for the orchestration of mucosal immunity during both bacterial infection and colitis. This work expands our interpretation of the protein-coding genome and demonstrates that proteinaceous products generated from non-canonical ORFs are crucial for the immune response in vivo. We therefore propose that the misannotation of non-canonical ORF-containing genes as non-coding RNAs may obscure the essential role of a multitude of previously undiscovered protein-coding genes in immunity and disease.