Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles.

Inhibition of disease-causing mutations using RNA interference (RNAi) has resulted in clinically approved medicines with additional candidates in late stage trials. However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non-liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided.

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days.

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells.

Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models.

Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.

Chimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B-cell lymphoma (BL). However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment. Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used.

The interplay of quaternary ammonium lipid structure and protein corona on lung-specific mRNA delivery by selective organ targeting (SORT) nanoparticles.

Messenger RNA (mRNA) can treat genetic disease using protein replacement or genome editing approaches but requires a suitable carrier to circumnavigate biological barriers and access the desired cell type within the target organ. Lipid nanoparticles (LNPs) are widely used in the clinic for mRNA delivery yet are limited in their applications due to significant hepatic accumulation because of the formation of a protein corona enriched in apolipoprotein E (ApoE). Our lab developed selective organ targeting (SORT) LNPs that incorporate a supplementary component, termed a SORT molecule, for tissue-specific mRNA delivery to the liver, spleen, and lungs of mice.

Unrevealing the potential of microbes in decomposition of organic matter and release of carbon in the ecosystem.

Organic matter decomposition is a biochemical process with consequences affecting climate change and ecosystem productivity. Once decomposition begins, C is lost as CO or sequestered into more recalcitrant carbon difficult to further degradation. As microbial respiration releases carbon dioxide into the atmosphere, microbes act as gatekeepers in the whole process.

Fuzzy logic, geostatistics, and multiple linear models to evaluate irrigation metrics and their influencing factors in a drought-prone agricultural region.

The quality of water used for irrigation is one of the major threats to maintaining the long-term sustainability of agricultural practices. Although some studies have addressed the suitability of irrigation water in different parts of Bangladesh, the irrigation water quality in the drought-prone region has yet to be thoroughly studied using integrated novel approaches. This study aims to assess the suitability of irrigation water in the drought-prone agricultural region of Bangladesh using traditional irrigation metrics such as sodium percentage (NA%), magnesium adsorption ratio (MAR), Kelley's ratio (KR), sodium adsorption ratio (SAR), total hardness (TH), permeability index (PI), and soluble sodium percentage (SSP), along with novel irrigation indices such as irrigation water quality index (IWQI) and fuzzy irrigation water quality index (FIWQI).

Lipid Nanoparticle (LNP) Chemistry Can Endow Unique RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model.

Within the field of lipid nanoparticles (LNPs) for RNA delivery, the focus has been mainly placed on organ level delivery, which can mask cellular level effects consequential to therapeutic applications. Here, we studied a pair of LNPs with similar physical properties and discovered how the chemistry of the ionizable amino lipid can control the endogenous LNP identity, affecting cellular uptake in the liver and altering therapeutic outcomes in a model of liver cancer. Although most LNPs accumulate in the liver after intravenous administration (suggesting that liver delivery is straightforward), we observed an unexpected behavior when comparing two similar LNP formulations (5A2-SC8 and 3A5-SC14 LNPs) that resulted in distinct RNA delivery within the organ.

Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes.

Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes . This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers.

Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity.

Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses.

Nuclear FGFR1 Regulates Gene Transcription and Promotes Antiestrogen Resistance in ER Breast Cancer.

Purpose: FGFR1 overexpression has been associated with endocrine resistance in ER breast cancer. We found FGFR1 localized in the nucleus of breast cancer cells in primary tumors resistant to estrogen suppression. We investigated a role of nuclear FGFR1 on gene transcription and antiestrogen resistance.

Paracrine Crosstalk between Fibroblasts and ER Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes Tumor Growth.

Breast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER) breast cancer cells, which results in the creation of an interleukin (IL)-1β-enriched microenvironment.

Water vapor flux in tropical lowland rice.

A field experiment was conducted at Indian Council of Agricultural Research-National Rice Research Institute, Cuttack, Odisha, India in the dry seasons of 2015 and 2016 to assess the water vapor flux (FHO) and its relationship with other climatic variables. The FHO and climatic variables were measured by an eddy covariance system and a micrometeorological observatory. Daily mean FHO during the dry seasons of 2015 and 2016 were 0.

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells.

Background/aims: Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-α positive (ER+) breast cancer tumours. Unfortunately, development of endocrine therapy resistance (ETR) is a frequent event resulting in disease relapse and decreased overall patient survival. The long noncoding RNA, H19, was previously shown to play a significant role in estrogen-induced proliferation of both normal and malignant ER+ breast epithelial cells.

A robust cell culture system for large scale feeder cell-free expansion of human breast epithelial progenitors.

Background: Normal human breast epithelial cells are maintained by the proliferation and differentiation of different human breast epithelial progenitors (HBEPs). However, these progenitor subsets can only be obtained at low frequencies, limiting their further characterization. Recently, it was reported that HBEPs can be minimally expanded in Matrigel cocultures with stromal feeder cells.

Greenhouse gas emissions and energy exchange in wet and dry season rice: eddy covariance-based approach.

Lowland tropical rice-rice system has a unique micrometrological characteristic that affects both energy component and net ecosystem energy. Periodic and seasonal variations of methane (CH), carbon dioxide (CO), and energy exchange from irrigated lowland rice-rice ecosystem were studied using open-path eddy covariance (EC) system during the dry (DS) and wet (WS) seasons in 2015. Concurrently, the manual chamber method was employed in nitrous oxide (NO) measurement efflux.

Breast Cancers Activate Stromal Fibroblast-Induced Suppression of Progenitors in Adjacent Normal Tissue.

Human breast cancer cells are known to activate adjacent "normal-like" cells to enhance their own growth, but the cellular and molecular mechanisms involved are poorly understood. We now show by both phenotypic and functional measurements that normal human mammary progenitor cells are significantly under-represented in the mammary epithelium of patients' tumor-adjacent tissue (TAT). Interestingly, fibroblasts isolated from TAT samples showed a reduced ability to support normal EGF-stimulated mammary progenitor cell proliferation in vitro via their increased secretion of transforming growth factor β.

Adipose-Derived Stromal Vascular Fraction Differentially Expands Breast Progenitors in Tissue Adjacent to Tumors Compared to Healthy Breast Tissue.

Background: Autologous fat grafts supplemented with adipose-derived stromal vascular fraction are used in reconstructive and cosmetic breast procedures. Stromal vascular fraction contains adipose-derived stem cells that are thought to encourage wound healing, tissue regeneration, and graft retention. Although use of stromal vascular fraction has provided exciting perspectives for aesthetic procedures, no studies have yet been conducted to determine whether its cells contribute to breast tissue regeneration.

Estrogen regulates luminal progenitor cell differentiation through H19 gene expression.

Although the role of estrogen signaling in breast cancer development has been extensively studied, the mechanisms that regulate the indispensable role of estrogen in normal mammary gland development have not been well studied. Because of the unavailability of culture system to maintain estrogen-receptor-positive (ERα(+)) cells in vitro, the molecular mechanisms that regulate estrogen/ERα signaling in the normal human breast are unknown. In the present study, we examined the effects of estrogen signaling on ERα(+) human luminal progenitors using a modified matrigel assay and found that estrogen signaling increased the expansion potential of these progenitors.

Coexistence of pulmonary tuberculosis and sarcoidosis: a diagnostic dilemma.

Tuberculosis and sarcoidosis are multisystem diseases having different aetiology and management; however, they have similar clinical and histological characteristics. Very rarely they may coexist. We report a rare case of a 38-year-old woman who presented with chronic cough, low-grade fever and respiratory distress that was initially diagnosed as miliary tuberculosis.

Isolated splenic tuberculosis in an immunocompetent patient.

A 20-year-old woman presented with fever and was eventually diagnosed with splenic tuberculosis as the sole site of the disease. Laboratory data gave no specific information for diagnosis except for a raised erythrocyte sedimentation rate and mild anaemia. Abdominal ultrasonography revealed splenomegaly with multiple hypoechoic lesions within it.

Loss of Igfbp7 causes precocious involution in lactating mouse mammary gland.

Background: Insulin like growth factors (IGFs) and their binding proteins (IGFBPs) are secreted peptides that play major roles in regulating the normal development and maturation of mammary gland. While Igfbp7 has been shown to decrease breast tumor growth, its role in regulating the normal mammary gland development has not been studied. To this end, we generated Igfbp7-null mice and examined the development and maturation of mammary glands in the virgin, pregnant and lactating animals.

A study on blood culture positivity and C-reactive protein variability in neonatal septicaemia at neonatal intensive care unit of a tertiary care hospital.

Neonatal septicaemia is an important cause of neonatal morbidity and mortality. Blood culture is the gold standard for diagnosis of neonatal septicaemia. Several laboratory investigations are available to detect neonatal sepsis, one important is 'sepsis screen' which includes C-reactive protein (CRP), micro -ESR, total WBC count including immature to mature (VT) ratio and absolute neutrophil count.