PubMed | Viogen Biosciences, Llc, Orthobond, New Hope Baptist Church, Arup and 10 more.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2015
Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation.
PubMed | Cancer Research UK Research Institute, The Royal Marsden National Health Service NHS Foundation Trust, Epic Sciences, Inc., Genentech and Core Diagnostics
Type: Journal Article | Journal: British journal of cancer | Year: 2015
PTEN gene loss occurs frequently in castration-resistant prostate cancer (CRPC) and may drive progression through activation of the PI3K/AKT pathway. Here, we developed a novel CTC-based assay to determine PTEN status and examined the correlation between PTEN status in CTCs and matched tumour tissue samples.PTEN gene status in CTCs was evaluated on an enrichment-free platform (Epic Sciences) by fluorescence in situ hybridisation (FISH). PTEN status in archival and fresh tumour tissue was evaluated by FISH and immunohistochemistry.Peripheral blood was collected from 76 patients. Matched archival and fresh cancer tissue was available for 48 patients. PTEN gene status detected in CTCs was concordant with PTEN status in matched fresh tissues and archival tissue in 32 of 38 patients (84%) and 24 of 39 patients (62%), respectively. CTC counts were prognostic (continuous, P=0.001). PTEN loss in CTCs associated with worse survival in univariate analysis (HR 2.05; 95% CI 1.17-3.62; P=0.01) and with high lactate dehydrogenase (LDH) in metastatic CRPC patients.Our results illustrate the potential use of CTCs as a non-invasive, real-time liquid biopsy to determine PTEN gene status. The prognostic and predictive value of PTEN in CTCs warrants investigation in CRPC clinical trials of PI3K/AKT-targeted therapies.
PubMed | Kalinga Hospital, Core Diagnostics and University of Pittsburgh
Type: Journal Article | Journal: Pathology, research and practice | Year: 2015
IgG4-related disease (IgG4-RD) is a recently recognized systemic autoimmune disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive plasma cells in multiple organs. The condition was first described as a disease of the pancreas, and has since been recognized in various organ systems including the kidneys. IgG4 related kidney disease (IgG4-RKD) signifies any form of renal involvement by IgG4-RD. The most common renal involvement by IgG4-RD is tubulointerstitial nephritis. Glomerular disease, in particular membranous glomerulonephritis, may also be seen. Other co-existent glomerular diseases such as IgA nephropathy, membranoproliferative glomerulonephritis, and mesangioproliferative immune complex glomerulonephritis may be identified. IgG4-related plasma cell arteritis has also been noted in the kidney. As with IgG4-RD in general, IgG4 related kidney disease (IgG4-RKD) usually occurs in middle-aged to elderly men. Common findings in IgG4-RKD are plasma cell-rich interstitial inflammatory infiltrate either in a focal or diffuse pattern with increased IgG4+ plasma cells, expansile swirling interstitial fibrosis, high levels of serum IgG and IgG4, hypocomplementemia, high serum IgE levels and/or peripheral blood eosinophilia. By immunofluorescence, most of the cases show IgG4 dominant tubular basement membrane immune complex deposits. Similar to IgG4-RD, IgG4-RKD often shows a rapid response to steroid therapy. In this review, we discuss the current knowledge on IgG4-RKD and its clinical relevance.
PubMed | Core Diagnostics and Kaohsiung Chang Gung Memorial Hospital
Type: Journal Article | Journal: Journal of molecular medicine (Berlin, Germany) | Year: 2016
Articular cartilage integrity loss is a prominently deleterious feature of osteoarthritis (OA). The mechanistic underlying the development of OA warrants characterization. Heat shock proteins (HSPs), members of the chaperone family, reportedly orchestrate tissue homeostasis and remodeling in response to detrimental stress. This study was undertaken to characterize the biological role of HSP60 in the pathogenesis of OA knee. Articular specimens from OA knee patients displayed severe articular damage histopathology concomitant with low HSP60 concentrations in cartilage and synovial fluid compared to non-OA patients. In vitro, a gain of HSP60 signaling counteracted the IL-1-mediated suppression of mitochondrial biogenesis, chondrogenic transcription factor SOX9, and cartilage matrix expression of human chondrocytes cultures. Transgenic mice that overexpressed human HSP60 (TgHSP60) had higher chondrocyte proliferation and thicker articular cartilage than wild-type mice. In collagenase-induced OA knees, analyses of CatWalk, 2-deoxyglucose-probed fluorescence imaging, and CT revealed that affected knees of TgHSP60 mice showed minor footprint irregularity, joint inflammation, and osteophyte formation. HSP60 overexpression also alleviated the histopathology of cartilage damage, synovial hypervascularization, and macrophage infiltration within joint lesions. Intra-articular administration of exogenous HSP60 ameliorated the pathogenesis of cartilage deterioration, synovitis, and osteophyte accumulation, thereby improving gait profiles of the collagenase-injured knees. HSP60 signaling maintains SOX9 levels by attenuating SOX9 hyper-ubiquitination of affected joints. Taken together, HSP60 deficiency in articular compartments was relevant to OA knee incidence. Sustained HSP60 signaling is favorable to mitigate the progression of OA. This study highlights the joint-anabolic actions of HSP60 and provides perspective on its therapeutic potential for OA.HSP60 deficiency is relevant to the existence of end-stage knee osteoarthritis. HSP60 overexpression attenuates cartilage matrix loss of inflammatory chondrocytes. HSP60 transgenic mice showed mild articular injury during knee osteoarthritis. HSP60 maintains knee joint homeostasis through reducing SOX9 ubiquitination. Control of cartilage-anabolic regulator HSP60 ameliorates knee osteoarthritis.
PubMed | Core Diagnostics
Type: Journal Article | Journal: Bosnian journal of basic medical sciences | Year: 2015
The development of antibiotics changed the world of medicine and has saved countless human and animal lives. Bacterial resistance/tolerance to antibiotics have spread silently across the world and has emerged as a major public health concern. The recent emergence of pan-resistant bacteria can overcome virtually any antibiotic and poses a major problem for their successful control. Selection for antibiotic resistance may take place where an antibiotic is present: in the skin, gut, and other tissues of humans and animals and in the environment.Borrelia burgdorferi, the etiological agents of Lyme borreliosis, evades host immunity and establishes persistent infections in its mammalian hosts. The persistent infection poses a challenge to the effective antibiotic treatment, as demonstrated in various animal models. An increasingly heterogeneous subpopulation of replicatively attenuated spirochetes arises following treatment, and these persistent antimicrobial tolerant/resistant spirochetes are non-cultivable. The non-cultivable spirochetes resurge in multiple tissues at 12 months after treatment, with B. burgdorferi-specific DNA copy levels nearly equivalent to those found in shame-treated experimental animals. These attenuated spirochetes remain viable, but divide slowly, thereby being tolerant to antibiotics. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, spirochetes were acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues. A number of host cytokines were up- or down-regulated in tissues of both shame- and antibiotic-treated mice in the absence of histopathology, indicating a lack of host response to the presence of antimicrobial tolerant/resistant spirochetes.
PubMed | Core Diagnostics
Type: Journal Article | Journal: Pathology, research and practice | Year: 2015
Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare morphologic entity. This tumor is usually associated with familial adenomatous polyposis (FAP), but rarely may be sporadic. This neoplasm commonly occurs in young females. The majority of patients present with gradually enlarging painless neck mass. There is no specific imaging finding of CMV-PTC, and the diagnosis is exclusively made on pathologic examination. A multitude of cytologic features of CMV-PTC are described, which includes hypercellularity, cribriform pattern, papillary arrangement of tall columnar cells, morules, spindle cells, clear and ground-glass nuclei, hyaline material, hemosiderin-laden histiocytes, and absence of colloid in the background. CMV-PTC is histologically characterized by the papillary growth of tall columnar cells, cribriform pattern without colloid, spindle cells, squamoid morules, and nuclear clearing. The immunoreactivity for beta-catenin and biotin-positive nuclear clearing may indicate CMV-PTC. Total thyroidectomy for familial or lobectomy for sporadic cases is usually the treatment for CMV-PTC. It carries a better prognosis than the other aggressive variants of papillary thyroid carcinoma. In this review, we discuss the current knowledge on CMV-PTC and its clinical relevance.
PubMed | Core Diagnostics and University of Pittsburgh
Type: Journal Article | Journal: Pathology, research and practice | Year: 2016
The Philadelphia (Ph) chromosome is infrequently found in acute lymphoblastic leukemia and is associated with poor prognosis. We present a case of Ph chromosome positive B cell-acute lymphoblastic leukemia with the partial trisomy of chromosome 1q involving chromosome 13 as the acceptor which has never been reported in the English literature. Jumping translocation (JT) of chromosome 1 is rare and is associated with disease progression and poor prognosis. Herein, we report the first case of Ph chromosome positive B cell-acute lymphoblastic leukemia with coexisting jumping translocation of chromosome 1 leading to trisomy of chromosome 1q. Dismal prognosis associated with synchronous presence of a Ph chromosome and JT leading to a partial trisomy of chromosome 1q may carry significant prognostic and therapeutic implications. This may be an incidental finding and further studies with large patient cohorts and clinical outcomes are needed to definitively determine the predictive value of this cytogenetic finding.
News Article | February 20, 2014
When we say India is a land of opportunity, there are a few sectors where this opportunity is more visible than others. Healthcare is a sector that holds promise. While healthcare is a broad area of opportunity, different verticals within the space have more potential. KPMG has pegged the healthcare diagnostics market to be worth $2.5 billion in 2012 and to grow in the region of 18-20% in the coming few years. And while there are well-known names in the usual diagnostics space, esoteric or specialised diagnostics is still an open field. It is in this green field that young Zoya Brar has set out to seek her fortune. The 24-year-old Zoya got hired by Google fresh out of college. She, however, quit in two years in March 2013 to found Core Diagnostics – a clinical laboratory focused on next generation diagnostics for disease stratification and therapy selection. If you thought starting up in clinical diagnostics was a tough task, try telling this young girl that. Zoya, who is the youngest member in the team, says the way Core Diagnostics is different from the other diagnostic chains is because of its emphasis on being innovative. So within a few months of launching, the first thing Core Diagnostics has done is merge with Palo Alto, US-based diagnostics chain OncoMDx. This move was important to get access to the expertise of histo pathologists and super specialists who work in the US, says Zoya. “We could have always sent the patient report to the US for testing but that would have resulted in high costs for the customer. Instead, through this merger they now have access to experts sitting in the US, who can offer their services to Indian patients are a little incremental cost,[V1] ” she says. Core Diagnostics will leverage its partnership with OncoMDx to help patients who use Core Diagnostics services in India. Zoya says their focus is esoteric diagnostic because there exists a big gap in supply and demand in that space. She narrates an example of a woman who had a benign tumour in her breast, but was treated for breast cancer and also had to undergo mastectomy due to wrong diagnosis. “That lady didn’t even need any treatment, but had to undergo so much mental and physical trauma because of wrong diagnosis,” explains Zoya. Another reference she cites is the emergence of branded hospital chains in India over the last few years. “If you go back 10 years and see how healthcare delivery has evolved in India all the hospitals that are well-known today, didn’t exist back then. We were living with what was available. Then hospitals like Fortis came to India resulting in a change in customer demand. If you had asked people 15 years ago whether this will work, they would have said it is too high end and we don’t need it. But today the scenario has changed. This is how esoteric diagnostics will also evolve,” she reasons. India will be the main market for Core Diagnostics, but going forward they will offer services in the US as well. Besides their panel of specialists in the US, Core Diagnostic has a team of 30 in India who handle affairs of the startup here. The team is a mix of people from various backgrounds, including pharma, medical devices, IT and healthcare delivery among others. “If you go to other pathologies, there is a certain way they hire. But clearly those labs are not doing all the things right. So we wanted a team from different backgrounds so as to allow lot of innovation to happen on a daily basis,” reasons Zoya. The startup has taken the below-the-line approach to publicise itself and Zoya says they will continue with this strategy for some time. One-to-one meetings with doctors to inform them about Core Diagnostic are also being adopted. Zoya says expanding to all major metros within India is on the cards in the near future. However, as they grow their expansion strategy will be three-pronged – on geography, technology and clinical options. Geographic expansion will mostly be through company-owned outlets so that the quality of service delivery can be well-managed. Core Diagnostics received a funding of $5 million from Artiman Ventures in the beginning and is on the lookout for fresh funding. While the journey has had its share of challenges, Zoya admits that hiring was the biggest of them all. It did not help that people in the diagnostics industry are mostly senior professionals and a 20-year-old taking their job interview was not something they had expected. Zoya found a way to work around this problem by getting her VCs and advisory board members to conduct the interviews. “Talking to VCs is the easy part because they like to invest in people, not the idea or the company. But yes, hiring team members was a challenge. We used some tricks in the book, but managed to do a good job,” she says.
News Article | February 23, 2014
Did you read about the Flipkart-Myntra acquisition and other top stories of the week? Last week (19th May – 24th May) will go down in the history of Indian startup ecosystem as the one to witness the largest ecommerce (India) deal of all time times taking place. The poster boys of Indian ecommerce industry, Sachin-Binny Bansal welcomed the third Bansal (Mukesh Bansal, Founder – Myntra) to lead their fashion […]