Establishment, molecular and biological characterization of HCB-514: a novel human cervical cancer cell line

Cervical cancer is the fourth most common cancer in women. Although cure rates are high for early stage disease, clinical outcomes for advanced, metastatic, or recurrent disease remain poor. To change this panorama, a deeper understanding of cervical cancer biology and novel study models are needed. Immortalized human cancer cell lines such as HeLa constitute crucial scientific tools, but there are few other cervical cancer cell lines available, limiting our understanding of a disease known for its molecular heterogeneity. This study aimed to establish novel cervical cancer cell lines derived from Brazilian patients. We successfully established one (HCB-514) out of 35 cervical tumors biopsied. We confirmed the phenotype of HCB-514 by verifying its' epithelial and tumor origin through cytokeratins, EpCAM and p16 staining. It was also HPV-16 positive. Whole-exome sequencing (WES) showed relevant somatic mutations in several genes including BRCA2, TGFBR1 and IRX2. A copy number variation (CNV) analysis by nanostring and WES revealed amplification of genes mainly related to kinases proteins involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and validated by western blot analysis. Furthermore, the HCB-514 cell line was sensitive to cisplatin. In summary, this novel Brazilian cervical cancer cell line exhibits relevant key molecular features and constitutes a new biological model for pre-clinical studies.Barretos Cancer Hospital Research Support Department (NAP) for sample collection, Barretos Cancer Hospital Biobank for sample processing, Dr. Flávia de Paula and Gabriela Fernandes for technical support of STRs and BRCA2 Sanger validation, respectively, and Dr. Laura Musselwhite (Duke University) for revising the manuscript. This study was supported by grants from the FINEP (MCTI/FINEP/MS/SCTIE/DECIT-01/2013 - FPXII- BIOPLAT - Process number 01.13.0469.00) and Barretos Cancer Hospital. PhD scholarship from FINEP (Grant numbers 384088/2014-7 and 380434/2015-6) and Barretos Cancer Hospital to MNR

Beneficial Effect of Consecutive Screening Mammography Examinations on Mortality from Breast Cancer: A Prospective Study

BackgroundPreviously, the risk of death from breast cancer was analyzed for women participating versus those not participating in the last screening examination before breast cancer diagnosis. Consecutive attendance patterns may further refine estimates.PurposeTo estimate the effect of participation in successive mammographic screening examinations on breast cancer mortality.Materials and MethodsParticipation data for Swedish women eligible for screening mammography in nine counties from 1992 to 2016 were linked with data from registries and regional cancer centers for breast cancer diagnosis, cause, and date of death (Uppsala University ethics committee registration number: 2017/147). Incidence-based breast cancer mortality was calculated by whether the women had participated in the most recent screening examination prior to diagnosis only (intermittent participants), the penultimate screening examination only (lapsed participants), both examinations (serial participants), or neither examination (serial nonparticipants). Rates were analyzed with Poisson regression. We also analyzed incidence of breast cancers proving fatal within 10 years.ResultsData were available for a total average population of 549 091 women (average age, 58.9 years ± 6.7 [standard deviation]). The numbers of participants in the four groups were as follows: serial participants, 392 135; intermittent participants, 41 746; lapsed participants, 30 945; and serial nonparticipants, 84 265. Serial participants had a 49% lower risk of breast cancer mortality (relative risk [RR], 0.51; 95% CI: 0.48, 0.55; P P ConclusionWomen participating in the last two breast cancer screening examinations prior to breast cancer diagnosis had the largest reduction in breast cancer death. Missing either one of the last two examinations conferred a significantly higher risk.Published under a CC BY 4.0 license.</p

Recent trends in specialty pharma business model

The recent rise of specialty pharma is attributed to its flexible, versatile, and open business model while the traditional big pharma is facing a challenging time with patent cliff, generic threat, and low research and development (R&D) productivity. These multinational pharmaceutical companies, facing a difficult time, have been systematically externalizing R&D and some even establish their own corporate venture capital so as to diversify with more shots on goal, with the hope of achieving a higher success rate in their compound pipeline. Biologics and clinical Phase II proof-of-concept (POC) compounds are the preferred licensing and collaboration targets. Biologics enjoys a high success rate with a low generic biosimilar threat, while the need is high for clinical Phase II POC compounds, due to its high attrition/low success rate. Repurposing of big pharma leftover compounds is a popular strategy but with limitations. Most old compounds come with baggage either in lackluster clinical performance or short in patent life. Orphan drugs is another area which has gained popularity in recent years. The shorter and less costly regulatory pathway provides incentives, especially for smaller specialty pharma. However, clinical studies on orphan drugs require a large network of clinical operations in many countries in order to recruit enough patients. Big pharma is also working on orphan drugs starting with a small indication, with the hope of expanding the indication into a blockbuster status. Specialty medicine, including orphan drugs, has become the growth engine in the pharmaceutical industry worldwide. Big pharma is also keen on in-licensing technology or projects from specialty pharma to extend product life cycles, in order to protect their blockbuster drug franchises. Ample opportunities exist for smaller players, even in the emerging countries, to collaborate with multinational pharmaceutical companies provided that the technology platforms or specialty medicinal products are what the big pharma wants. The understanding of intellectual properties and international drug regulations are the key for specialty pharma to have a workable strategy for product registration worldwide

Continental transmission of emerging COVID-19 on the 38° north latitude

Background: As COVID-19 has become a pandemic emerging infectious disease it is important to examine whether there was a spatiotemporal clustering phenomenon in the globe during the rapid spread after the first outbreak reported from southern China. Materials and methods: The open data on the number of COVID-19 cases reported at daily basis form the globe were used to assess the evolution of outbreaks with international air link on the same latitude and also including Taiwan. The dynamic Susceptible-Infected-Recovered model was used to evaluate continental transmission from December 2019 to March 2020 before the declaration of COVID-19 pandemic with basic reproductive number and effective reproductive number before and after containment measurements. Results: For the initial COVID-19 outbreak in China, the estimated reproductive number was reduced from 2.84 during the overwhelming outbreaks in early January to 0.43 after the strict lockdown policy. It is very surprising to find there were three countries (including South Korea, Iran, and Italy) and the Washington state of the USA on the 38° North Latitude involved with large-scale community-acquired outbreaks since the first imported COVID-19 cases from China. The propagation of continental transmission was augmented from hotspot to hotspot with higher reproductive number immediately before the declaration of pandemic. By contrast, there was not any large community-acquired outbreak in Taiwan. Conclusion: The propagated spatiotemporal transmission from China to other hotspots may explain the emerging pandemic that can only be exempted by timely border control and preparedness of containment measurements according to Taiwan experience

Use of the Biopharmaceutical Classification System in Early Drug Development

The Biopharmaceutics Classification System (BCS) is not only a useful tool for obtaining waivers for in-vivo bioequivalence studies but also for decision making in the discovery and early development of new drugs. Measurement of solubility and permeability in the discovery/development settings is described. These data can be utilized for the preliminary BCS classification of pipeline compounds. A decision tree is described in the prioritization of salt and polymorph screening studies prior to in vivo studies in animals. For BCS class 1 and 3 compounds, polymorphism is less likely to impact on bioavailability. The polymorph screening study may be postponed after animal studies. The BCS classification can also be used in the design of animal and human formulations. A BCS-based animal formulation development decision tree is presented. A compound is triaged based on a series of decision points into one of the five formulation strategies. Human formulation has different requirements than animal formulation. A comparison between animal and human formulation strategies is presented. In conclusion, for non-BCS 1 compounds, the right-first-time polymorph and formulation selection ensures consistent pharmacokinetic performance and avoids bridging BA/BE studies. It is in line with FDA’s initiative to reduce R&D cycle time through quality by design for pharmaceutical products