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Decorin and biglycan are two small leucine-rich proteoglycans (SLRPs) that regulate collagen fibrillogenesis and extracellular matrix assembly in tendon. The objective of this study was to determine the individual roles of these molecules in maintaining the structural and mechanical properties of tendon during homeostasis in mature mice. We hypothesized that knockdown of decorin in mature tendons would result in detrimental changes to tendon structure and mechanics while knockdown of biglycan would have a minor effect on these parameters. To achieve this objective, we created tamoxifen-inducible mouse knockdown models targeting decorin or biglycan inactivation. This enables the evaluation of the roles of these SLRPs in mature tendon without the abnormal tendon development caused by conventional knockout models. Contrary to our hypothesis, knockdown of decorin resulted in minor alterations to tendon structure and no changes to mechanics while knockdown of biglycan resulted in broad changes to tendon structure and mechanics. Specifically, knockdown of biglycan resulted in reduced insertion modulus, maximum stress, dynamic modulus, stress relaxation, and increased collagen fiber realignment during loading. Knockdown of decorin and biglycan produced similar changes to tendon microstructure by increasing the collagen fibril diameter relative to wild-type controls. Biglycan knockdown also decreased the cell nuclear aspect ratio, indicating a more spindle-like nuclear shape. Overall, the extensive changes to tendon structure and mechanics after knockdown of biglycan, but not decorin, provides evidence that biglycan plays a major role in the maintenance of tendon structure and mechanics in mature mice during homeostasis.

Background Breast-conserving surgery is a critical step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to guide in real-time the removal of cancer missed during the initial lumpectomy to reduce the number of second operations. The pegulicianine imaging agent is injected intravenously before surgery and its fluorescence signal is activated by proteases in tumor cells and cells at the tumor margin. The LUM Imaging System visualizes activated pegulicianine in the lumpectomy cavity via a hand-held detector and proprietary tumor detection software. This system was previously tested in multiple single-site studies and a prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design and Specific Aims: The current prospective, multi-center, randomized, blinded study was designed to show the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to demonstrate guided removal of residual cancer in the lumpectomy missed during the initial procedure and potentially reduce the rates of positive margins. This study is powered by an event-driven design that requires 70 truth-standard positive events. It is expected that approximately 390 women at fourteen medical centers across the US will be enrolled to achieve the number of events. Pegulicianine is injected 2-6 hours prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy followed by blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that have positive LUM signal. Pathologists are blinded to the source of tissue removed (SOC vs. LUM) when conducting the pathology assessment. The amount of additional tissue volume resected is also evaluated. Patient reported outcome data is collected as a quality-of-life survey before and after the subject’s lumpectomy.Eligibility Criteria: This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Patients must not have a history of allergic reaction to polyethylene glycol, contrast agents, or have received neoadjuvant therapy to treat their current breast cancer. Use of blue dyes before imaging with the LUM System are not allowed. Additional detailed eligibility criteria are listed in the protocol. Accrual and Study Progress To date, 350 subjects have participated in this trial. This study is funded in part by the National Cancer Institute (5R44CA211013). This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, Marie Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal study of the Lum imaging system for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer: The INCITE trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-12-03.

Supplementary Method Descriptions Molecular modeling and computational studies Enzyme expression and purification. In vitro enzymatic assays and Ki determinations In vivo efficacy trials with MIA PaCa-2 pancreatic cancer xenografts. Cytochrome c oxidase assay Synthesis of AGF94 and 5-substituted pyrrolo[3,2-d]pyrimidine compounds

Folate-dependent one-carbon (C1) metabolism is compartmentalized into the mitochondria and cytosol and supports cell growth through nucleotide and amino acid biosynthesis. Mitochondrial C1 metabolism, including serine hydroxymethyltransferase (SHMT) 2, provides glycine, NAD(P)H, ATP, and C1 units for cytosolic biosynthetic reactions, and is implicated in the oncogenic phenotype across a wide range of cancers. Whereas multitargeted inhibitors of cytosolic C1 metabolism, such as pemetrexed, are used clinically, there are currently no anticancer drugs that specifically target mitochondrial C1 metabolism. We used molecular modeling to design novel small-molecule pyrrolo[3,2-d]pyrimidine inhibitors targeting mitochondrial C1 metabolism at SHMT2. In vitro antitumor efficacy was established with the lead compounds (AGF291, AGF320, AGF347) toward lung, colon, and pancreatic cancer cells. Intracellular targets were identified by metabolic rescue with glycine and nucleosides, and by targeted metabolomics using a stable isotope tracer, with confirmation by in vitro assays with purified enzymes. In addition to targeting SHMT2, inhibition of the cytosolic purine biosynthetic enzymes, β-glycinamide ribonucleotide formyltransferase and/or 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase, and SHMT1 was also established. AGF347 generated significant in vivo antitumor efficacy with potential for complete responses against both early-stage and upstage MIA PaCa-2 pancreatic tumor xenografts, providing compelling proof-of-concept for therapeutic targeting of SHMT2 and cytosolic C1 enzymes by this series. Our results establish structure–activity relationships and identify exciting new drug prototypes for further development as multitargeted antitumor agents.

Supplementary Figure S1 shows in vitro antiproliferative activity and targeted pathways of previously reported AICARFTase and GARFTase inhibitors. Supplementary Figure S2 shows docking of AGF291, AGF320, and AGF347 (along with 5-formyl-THF) in human SHMT2 and rabbit SHMT1. Supplementary Figure S3 shows plasma membrane folate transporter expression levels in H460, HCT116, and MIA PaCa-2 human tumor cell lines as compared to those in the IGROV-1 epithelial ovarian cancer cell line. Supplementary Figure S4 shows in vitro antiproliferative activity and targeted pathways of AGF291, AGF320, and AGF347 along with previously reported GARFTase inhibitor AGF94 in H460, HCT116, and MIA PaCa-2 cell lines. Supplementary Figure S5 shows targeted metabolomics data on total serine, serine isotope labeling patterns, total GAR, total AICAR, total adenine nucleotides, and total dTTP along with isotope labeling patterns of H460, HCT116, and MIA PaCa-2 cell lines treated with AGF291, AGF320, and AGF347 not shown in main text Figure 4. Supplementary Figure S6 shows a Western blot confirming knockdown of SHMT2 in H460 SHMT2 KD cell line and knockout of SHMT2 in HCT116 SHMT2 KO cell line. Supplementary Figure S7 shows in vivo efficacies of AGF347 and gemcitabine towards MIA PaCa-2 early and late stage tumor xenograft models where mouse serum folate levels were not depleted to approximate those found in humans. Supplementary Figure S8 shows a cytochrome c oxidase assay on tumors harvested from the metabolomics arm of the late stage in vivo AGF347 trial. Table S1 shows docking scores of novel compounds in human SHMT2 and rabbit SHMT1 (corresponding to Supplementary Figure S2). Table S2 shows quantitative data from in vivo early- and late-stage trials of AGF347 and gemcitabine against MIA PaCa-2 tumor xenografts in NCR SCID mice.

SARS CoV-2 i.e. Severe Acute Respiratory Syndrome Corona Virus-2 is the cause for spread of contagious COVID-19 (Corona Virus Disease-2019) in the world. According to resources, bats are the main source for SARS-CoV-2 communication, although the virus might have jumped from another transitional host to humans. COVID-19 was first diagnosed in Wuhan, China during end of December 2019 and has since increased progressively resulting in the current corona virus pandemic. The first case of COVID-19 in India was observed on 30th January 2020. Whereas the first case of COVID-19 in Indore (MP) was reported on 23rd March 2020 and since then it is increasing rapidly resulting in scores of casualties. Before the arrival of pandemic, Indore Administrative Department, Municipal Corporation, Health Department in co-operation with private hospitals were prepared to face the change. Jagadguru Dattatray Hospital & Research Center, Indore was one of the CDCP (Center for Disease Control & Prevention) and Isolation Centers in Indore. This paper highlights the challenges and strategies adopted by a hospital as an isolation center to fight against a world spread pandemic i.e. COVID-19.

BACKGROUND The Current National Comprehensive Cancer Network guidelines recommend modified radical mastectomy (MRM) as the surgical treatment of choice for nonmetastatic inflammatory breast cancer (IBC). Limited studies have looked into the outcomes of breast conserving surgery (BCS) vs. MRM for IBC. METHODS National Cancer Database (NCDB) data from 2004 to 2014 were retrospectively analyzed. Patients' demographics, tumor characteristics, and overall survival (OS) trends were compared for BCS and MRM cases of nonmetastatic IBC. Univariate and multivariate analyses were performed. RESULTS A total of 413 (3.89%) BCS and 10,197 (96.11%) MRM cases were identified. Median follow-up was 58.45 months. Compared to MRM, BCS patients were more likely to be older, be African American, have Medicare/Medicaid or be uninsured, live in lower education ZIP codes, and live in a metropolitan area (all p