Engineered collagen-targeting therapeutics reverse lung and kidney fibrosis in mice

Fibrotic diseases are involved in 45% of deaths in the United States. In particular, fibrosis of the kidney and lung are major public health concerns due to their high prevalence and lack of existing treatment options. Here, we harness the pathophysiological features of fibrotic diseases, namely leaky vasculature and aberrant extracellular matrix (ECM) protein deposition (i.e. collagen), to target an anti-fibrotic biologic and a small molecule drug to disease sites of fibrosis, thus improving their therapeutic potential in mouse models of lung and kidney fibrosis. First, we identify and validate collagen-targeting drug delivery systems that preferentially accumulate in the diseased organs: von Willebrand Factor's A3 domain (VWF-A3) and decorin-derived collagen-binding peptide-conjugated micelles (CBP-micelles). We then engineer and recombinantly express novel candidate biologic therapies based on the anti-inflammatory cytokine IL-10: A3-IL-10 and A3-Serum Albumin-IL-10 (A3-SA-IL-10). Simultaneously, we stably encapsulate the potential anti-fibrotic water-insoluble drug, rapamycin, in CBP-micelles. We show that these novel formulations of therapeutics bind to collagen in vitro and that their efficacy in mouse models of lung and kidney fibrosis is improved, compared to free, untargeted drugs. Our results demonstrate that collagen-targeted anti-fibrotic drugs may be next generation therapies of high clinical potential.

Nipple Aspirate Fluid at a Glance

Nipple aspirate fluid (NAF) is an intraductal mammary fluid that, because of its close proximity to and origin from the tissue from which breast cancer originates, is a promising source of biomarkers for early breast cancer detection. NAF can be non-invasively acquired via the nipple by aspiration using a suction device; using oxytocin nasal spray helps increase yield and tolerability. The aspiration procedure is generally experienced as more tolerable than the currently used breast imaging techniques mammography and breast magnetic resonance imaging. Future applications of NAF-derived biomarkers include their use as a tool in the detection of breast carcinogenesis at its earliest stage (before a tumor mass can be seen by imaging), or as a supporting diagnostic tool for imaging, such as when imaging is less reliable (to rule out false positives from imaging) or when imaging is not advisable (such as during pregnancy and breastfeeding). Ongoing clinical studies using NAF samples will likely shed light on NAF’s content and clinical potential. Here, we present a narrative review and perspectives of NAF research at a glance.

Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype

Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER−) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.

Animal Placental Therapy: An emerging tool for Health Care.

Background: The placenta maintains and regulates the growth of foetus and consists of various biologically active nutrients such as cytomedines, vitamins, trace elements, amino acids, peptides, growth factors and other biologically active constituents. Introduction: The therapeutic effectiveness of the placenta can be well defined with respect to several biochemical mechanisms of various components present in it. The placental extract derived from biomedical wastes has also shown a great potential for treatment of various diseases. Method: Placental therapy has been reported specifically to have potent action on treatment of diseases and tissue regeneration. Result: Placental bioactive components and their multi-targeting identity prompted us to compile the précised information on placental extract products. However, some findings are needed to be explored by scientific community to prove their clinical potential with significant statistical validation. Conclusion: In the light of available information and the usefulness of the placental extract, it is necessary that the formulations of various desirable properties may be developed to meet the clinical requirements in several treatment paradigms. It is also a matter of exploration that the short- and long-term adverse effects to be explored by advanced scientific techniques.

Integration of Genomic Profiling and Organoid Development in Precision Oncology

Precision oncology involves an innovative personalized treatment strategy for each cancer patient that provides strategies and options for cancer treatment. Currently, personalized cancer medicine is primarily based on molecular matching. Next-generation sequencing and related technologies, such as single-cell whole-transcriptome sequencing, enable the accurate elucidation of the genetic landscape in individual cancer patients and consequently provide clinical benefits. Furthermore, advances in cancer organoid models that represent genetic variations and mutations in individual cancer patients have direct and important clinical implications in precision oncology. This review aimed to discuss recent advances, clinical potential, and limitations of genomic profiling and the use of organoids in breast and ovarian cancer. We also discuss the integration of genomic profiling and organoid models for applications in cancer precision medicine.

Prevalence and clinical potential of extraspinal incidental findings in lumbosacral spine MRI of patients with suspected disc diseases

BACKGROUND Incidental findings could be observed in organs close to the spine while reporting lumbosacral spine magnetic resonance imaging (MRI). This study aimed to report the prevalence and clinical potential of extraspinal incidental findings in lumbosacral MRI of patients with suspected disc diseases. METHODS This single-centered cross-sectional study was carried out on 420 consecutive adult patients who underwent lumbar spine MRI for suspected disc disease from January to July 2019. The MRI was checked for the presence of extraspinal incidental findings, and each finding was categorized according to the body organ and its clinical significance. Each MRI plane that best displayed the findings was recorded, and the association between the findings and patient's age and sex was determined. RESULTS Of 420 samples, 135 cases showed extraspinal findings (32.1%), and 7.6% of the patients displayed suspicious lesions. The urinary tract was the most common system (18.6%) to display both clinically significant (5.0%) and benign findings (13.6%), and the axial MRI section was the plane which showed most of the incidental findings. Incidental findings in any body system were rarely found in the younger patients. Females had significantly higher benign findings than males (p = 0.002). CONCLUSIONS The prevalence of extraspinal findings in lumbosacral spine MRI is high, and some are significant. Most findings are related to the urinary tract and best displayed in the axial plane.

Integrated Proteomic and Metabolomic Analyses of the Mitochondrial Neurodegenerative Disease MELAS

MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical heterogeneity and the obscure genotype-phenotype correlation among MELAS patients. To gain insights into the pathogenic signature of MELAS, we designed a comprehensive strategy integrating proteomics and metabolomics in patient-derived dermal fibroblasts harboring the ultra-rare MELAS pathogenic variant m.14453G>A, specifically affecting the mitochondrial respiratory Complex I. Global proteomics was achieved by data-dependent acquisition (DDA) and verified by data-independent acquisition (DIA) using both Spectronaut and the recently launched MaxDIA platforms. Comprehensive metabolite coverage was achieved for both polar and nonpolar metabolites in both reverse phase and HILIC LC-MS/MS analyses. Our proof-of-principle MELAS study with multi-omics integration revealed OXPHOS dysregulation with a predominant deficiency of Complex I subunits, as well as alterations in key bioenergetic pathways, glycolysis, tricarboxylic acid cycle, and fatty acid β-oxidation. The most clinically relevant discovery is the downregulation of the arginine biosynthesis pathway, likely due to blocked argininosuccinate synthase, which is congruent with the MELAS cardinal symptom of stroke-like episodes and its current treatment by arginine infusion. In conclusion, we demonstrated an integrated proteomic and metabolomic strategy for patient-derived fibroblasts, which has great clinical potential to discover therapeutic targets and design personalized interventions after validation with a larger patient cohort in the future.

A Multi-Pronged Approach to Assessing Inflammatory Inhibitory Activity of a New Cyclic Alkaloid Compound from Root Bark of Ziziphus Nummularia (Aubrev.)

[(16-methoxy-10-(3-methyl-butyl)-2-oxa-6, 9, 12-triaza-tricyclo [13.3.1.03, 7] nonadeca-1(18), 13, 15 (19), 16-tetraene-8, 11-Dione], a putative cyclic alkaloid compound (IC) isolated from the root bark of Ziziphus nummularia, showed potential anti-inflammatory potential. Nitric oxide (NO), prostaglandin-E2 (PGE2), and tumour necrosis factor-alpha (TNF- α) levels were measured in vitro to assess IC's potential. ADME simulations and molecular docking of IC by TNF- α receptor were also performed. The in vivo potentials of IC and ethanolic extract (EE) were investigated by assessing carrageenan-induced paw oedema and arachidonic acid/xylene-induced ear oedema. TNF-α inhibition was higher in IC than in others, with a maximal percent inhibition of 88.00 percent at 50.11 µM. IC generated hydrogen bonds with ASP 45 and GLN 47, according to in silico research. Carrageenan, xylene, and arachidonic acid-induced oedema were all significantly reduced by IC. As a result, IC may have clinical potential in the future treatment of inflammation.