For success in biotechnology, look beyond biotechnology

1969 ◽  
Vol 16 (4) ◽  
Author(s):  
Yali Friedman
Keyword(s):  
Late Stage ◽  
Stock Price ◽  
Patent Protection ◽  
Early Stage ◽  
Corporate Sustainability ◽  
Biotechnology Industry ◽  
Biotechnology Companies ◽  
Near Term ◽  
The Impact

The fates of biotechnology companies can be fairly described as volatile. Clinical trial progress, patent grants and invalidations, and funding announcements can yield great swings in stock price. Building any company is a challenging endeavor, and these dramatic responses only compound the problem and complicate the management of biotechnology companies. Companies have employed a diversity of tactics to buffer the impact of individual setbacks – having multiple products in development, using a hybrid product/service strategy, and in-licensing externally partially developed leads are just a few.One consequence of these buffering strategies is reduced investor interest. The duration of biotechnology product development, combined with the long gap between funding and (potential) revenues, and the uncertainty of profitability encourage investors to favor either late-stage companies or those likely to ‘fail fast’. Late-stage companies often present more measurable investments than early-stage companies – and a shorter timeline to returns – and companies that can fail fast allow investors to conserve time and financial resources. The problem with these investment preferences is that for a company to mature to late-stage, it must find early- and mid-stage funding somewhere, and an excessive focus on failing fast is at odds with the long-term patient support needed for many projects.Therefore, how can biotechnology executives bridge the gap between biotechnology funding preferences, chaotic development progress and the sustained support needed for research projects? One answer is to seek opportunities in compatible industries. Seeking funding and revenue opportunities outside the biotechnology industry can effectively dissociate biotechnology companies from the negative constraints of the biotechnology industry, enabling them to mature in more supportive environments while still keeping a long-term focus on lucrative opportunities in biotechnology.Consider the example of Mission Motors. The company, which recently produced the world's fastest motorcycle, is not a motorcycle company; they used the motorcycle (which they are selling for nearly US$70 000 each) to help attract interest in their primary interest, which is software.1 BBK Technologies is an example from the biotechnology industry. BBK has applied fragment-matching algorithms from DNA sequence analysis to matching video sequences.2 With applications in stemming piracy and enabling image or video-based search, the technology clearly has robust applications beyond biotechnology. The extra biotechnology applications also serve as robust evidence of the utility of BBK's technology.What is not to like about these indirect paths? They can be slower than maintaining a strict focus on biotechnology-related goals. An oft-heard plea in biotechnology is the need for speed in development. Although it is true that patients may be suffering while treatments are in development, and that delays in development may result in a shorter duration of patent protection, a balance must still be maintained between speed of development and corporate sustainability. After all, an excess focus on near-term positive outcomes may lead to corporate collapse, likewise depriving patients of treatments. Leveraging opportunities outside of biotechnology to establish proof of principle or to build revenue streams can increase resilience, and can thereby provide a stronger foundation for corporate sustainability.References Dumaine, B. (2010) A motorcycle on a mission. Fortune, 14 June, p. 30.The physics arXiv blog. (2010) Sequencing the video genome. 31 March, http://arxiv.org/abs/1003.5320.

scholarly journals Adaptation to an amoeba host leads to Pseudomonas aeruginosa isolates with attenuated virulence

2022 ◽  
Author(s):  
Wai Leong ◽  
Wee Han Poh ◽  
Jonathan Williams ◽  
Carla Lutz ◽  
M. Mozammel Hoque ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Late Stage ◽  
Early Stage ◽  
Opportunistic Pathogen ◽  
Phenotypic Traits ◽  
Nucleotide Polymorphisms ◽  
Chronic Infections ◽  
The Impact

The opportunistic pathogen Pseudomonas aeruginosa , is ubiquitous in the environment, and in humans is capable of causing acute or chronic infections. In the natural environment, predation by bacterivorous protozoa represents a primary threat to bacteria. Here, we determined the impact of long-term exposure of P. aeruginosa to predation pressure. P. aeruginosa persisted when co-incubated with the bacterivorous Acanthamoeba castellanii for extended periods and produced genetic and phenotypic variants. Sequencing of late-stage amoeba-adapted P. aeruginosa isolates demonstrated single nucleotide polymorphisms within genes that encode known virulence factors and this correlated with a reduction in expression of virulence traits. Virulence towards the nematode, Caenorhabditis elegans , was attenuated in late-stage amoeba-adapted P. aeruginosa compared to early-stage amoeba-adapted and non-adapted counterparts. Further, late-stage amoeba-adapted P. aeruginosa showed increased competitive fitness and enhanced survival in amoeba as well as in macrophage and neutrophils. Interestingly, our findings indicate that the selection imposed by amoeba resulted in P. aeruginosa isolates with reduced virulence and enhanced fitness, similar to those recovered from chronic cystic fibrosis infections. Thus, predation by protozoa and long-term colonization of the human host may represent similar environments that select for similar losses of gene function. Importance Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute infections in plants and animals, including humans, and chronic infections in immunocompromised and cystic fibrosis patients. This bacterium is commonly found in soils and water where bacteria are constantly under threat of being consumed by bacterial predators, e.g. protozoa. To escape being killed, bacteria have evolved a suite of mechanisms that protect them from being consumed or digested. Here, we examine the effect of long-term predation on the genotypes and phenotypes expressed by P. aeruginosa . We show that long term co-incubation with protozoa resulted in mutations that resulted in P. aeruginosa becoming less pathogenic. This is particularly interesting as we see similar mutations arise in bacteria associated with chronic infections. Importantly, the genetic and phenotypic traits possessed by late-stage amoeba-adapted P. aeruginosa are similar to what is observed for isolates obtained from chronic cystic fibrosis infections. This notable overlap in adaptation to different host types suggests similar selection pressures amongst host cell types as well as similar adaptation strategies.

scholarly journals Lung Cancer Inequalities in Stage of Diagnosis in Ontario, Canada

2021 ◽  
Vol 28 (3) ◽  
pp. 1946-1956
Author(s):  
Aisha K. Lofters ◽  
Evgenia Gatov ◽  
Hong Lu ◽  
Nancy N. Baxter ◽  
Sara J. T. Guilcher ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Relative Risk ◽  
Late Stage ◽  
Early Stage ◽  
Small Cell ◽  
Cancer Type ◽  
Adjusted Relative Risk ◽  
Late Stage Diagnosis ◽  
Adjusted Model

Lung cancer is the most common cancer and cause of cancer death in Canada, with approximately 50% of cases diagnosed at stage IV. Sociodemographic inequalities in lung cancer diagnosis have been documented, but it is not known if inequalities exist with respect to immigration status. We used multiple linked health-administrative databases to create a cohort of Ontarians 40–105 years of age who were diagnosed with an incident lung cancer between 1 April 2012 and 31 March 2017. We used modified Poisson regression with robust standard errors to examine the risk of diagnosis at late vs. early stage among immigrants compared to long-term residents. The fully adjusted model included age, sex, neighborhood-area income quintile, number of Aggregated Diagnosis Group (ADG) comorbidities, cancer type, number of prior primary care visits, and continuity of care. Approximately 62% of 38,788 people with an incident lung cancer from 2012 to 2017 were diagnosed at a late stage. Immigrants to the province were no more likely to have a late-stage diagnosis than long-term residents (63.5% vs. 62.0%, relative risk (RR): 1.01 (95% confidence interval (CI): 0.99–1.04), adjusted relative risk (ARR): 1.02 (95% CI: 0.99–1.05)). However, in fully adjusted models, people with more comorbidities were less likely to have a late-stage diagnosis (adjusted relative risk (ARR): 0.82 (95% CI: 0.80–0.84) for those with 10+ vs. 0–5 ADGs). Compared to adenocarcinoma, small cell carcinoma was more likely to be diagnosed at a late stage (ARR: 1.29; 95% CI: 1.27–1.31), and squamous cell (ARR: 0.89; 95% CI: 0.87–0.91) and other lung cancers (ARR: 0.93; 95% CI: 0.91–0.94) were more likely to be diagnosed at an early stage. Men were also slightly more likely to have late-stage diagnosis in the fully adjusted model (ARR: 1.08; 95% CI: 1.05–1.08). Lung cancer in Ontario is a high-fatality cancer that is frequently diagnosed at a late stage. Having fewer comorbidities and being diagnosed with small cell carcinoma was associated with a late-stage diagnosis. The former group may have less health system contact, and the latter group has the lung cancer type most closely associated with smoking. As lung cancer screening programs start to be implemented across Canada, targeted outreach to men and to smokers, increasing awareness about screening, and connecting every Canadian with primary care should be system priorities.

scholarly journals The impact of Paenibacillus polymyxa HY96-2 luxS on biofilm formation and control of tomato bacterial wilt

2019 ◽  
Vol 103 (23-24) ◽  
pp. 9643-9657 ◽  
Author(s):  
Jincui Yi ◽  
Daojing Zhang ◽  
Yuejuan Cheng ◽  
Jingjing Tan ◽  
Yuanchan Luo
Keyword(s):  
Bacterial Wilt ◽  
Late Stage ◽  
Biofilm Formation ◽  
Early Stage ◽  
Regulatory Gene ◽  
Paenibacillus Polymyxa ◽  
Deletion Strain ◽  
Biocontrol Efficacy ◽  
The Impact ◽  
Tomato Bacterial Wilt

Abstract The focus of this study was to investigate the effects of luxS, a key regulatory gene of the autoinducer-2 (AI-2) quorum sensing (QS) system, on the biofilm formation and biocontrol efficacy against Ralstonia solanacearum by Paenibacillus polymyxa HY96-2. luxS mutants were constructed and assayed for biofilm formation of the wild-type (WT) strain and luxS mutants of P. polymyxa HY96-2 in vitro and in vivo. The results showed that luxS positively regulated the biofilm formation of HY96-2. Greenhouse experiments of tomato bacterial wilt found that from the early stage to late stage postinoculation, the biocontrol efficacy of the luxS deletion strain was the lowest with 50.70 ± 1.39% in the late stage. However, the luxS overexpression strain had the highest biocontrol efficacy with 75.66 ± 1.94% in the late stage. The complementation of luxS could restore the biocontrol efficacy of the luxS deletion strain with 69.84 ± 1.09% in the late stage, which was higher than that of the WT strain with 65.94 ± 2.73%. Therefore, we deduced that luxS could promote the biofilm formation of P. polymyxa HY96-2 and further promoted its biocontrol efficacy against R. solanacearum.

scholarly journals The Impact of International Sanctions on Russian Financial Markets

Economies ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 107
Author(s):  
Mirzosaid Sultonov
Keyword(s):  
Exchange Rate ◽  
Stock Price ◽  
Price Index ◽  
The United States ◽  
The European Union ◽  
Stock Price Index ◽  
The Exchange Rate ◽  
Long Term Impact ◽  
The Impact

Russia’s international comportment and geostrategic moves, particularly the invasion of Ukraine and the annexation of Crimea in 2014, caused a substantial change in its international economic and political relations. In response to Russia’s invasion, the United States of America, the European Union, and their allies imposed a series of sanctions. In this study, by applying an exponential generalized autoregressive conditional heteroscedasticity model to daily logarithmic returns of the ruble exchange rate and the closing price index of the Russian Trading System, we analyze how the returns and volatility of the exchange rate and the stock price index responded to the sanctions and oil price changes. The estimation results show that the sanctions have a significant positive short-term impact on exchange rate returns. Economic sanctions have a significant negative long-term impact on the returns and variance of the exchange rate and a significant positive long-term impact on the returns of the stock price index. Financial sanctions have a positive/negative long-term impact on the returns of the exchange rate/stock price index and a positive long-term impact on the variance of the exchange rate and the stock price index. Corporate sanctions have a positive long-term impact on exchange rate returns.

scholarly journals The Predicted Long-Term Benefits of Ensuring Timely Treatment and Medication Adherence in Early Schizophrenia

2019 ◽  
Vol 47 (3) ◽  
pp. 357-365
Author(s):  
Marcela Horvitz-Lennon ◽  
Zachary Predmore ◽  
Patrick Orr ◽  
Mark Hanson ◽  
Richard Hillestad ◽  
...  
Keyword(s):  
Early Stage ◽  
Competitive Employment ◽  
Independent Family ◽  
Treatment Entry ◽  
Adherence Intervention ◽  
Family Living ◽  
The Impact ◽  
Timely Treatment ◽  
Early Schizophrenia

AbstractThe impact of initiatives aimed at reducing time in untreated psychosis during early-stage schizophrenia will be unknown for many years. Thus, we simulate the effect of earlier treatment entry and better antipsychotic drug adherence on schizophrenia-related hospitalizations, receipt of disability benefits, competitive employment, and independent/family living over a ten-year horizon. We predict that earlier treatment entry reduces hospitalizations by 12.6–14.4% and benefit receipt by 7.0–8.5%, while increasing independent/family living by 41.5–46% and employment by 42–58%. We predict larger gains if a pro-adherence intervention is also used. Our findings suggest substantial benefits of timely and consistent early schizophrenia care.

scholarly journals Hepatitis C virus enhances Rubicon expression, leading to autophagy inhibition and intracellular innate immune activation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuto Shiode ◽  
Hayato Hikita ◽  
Satoshi Tanaka ◽  
Kumiko Shirai ◽  
Akira Doi ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Late Stage ◽  
Early Stage ◽  
Hcv Infection ◽  
Infected Cells ◽  
The Impact ◽  
Chronic Hepatitis C Patients

Abstract Autophagy, a degradation system, works to maintain cellular homeostasis. However, as the impact of Hepatitis C virus (HCV) infection on hepatocyte autophagy and its effect on HCV replication remain unclear, we examined them. HCV infection suppressed late-stage autophagy and increased Rubicon. siRNA-mediated knockdown of Rubicon promoted autophagy in HCV-infected cells. In Huh-7 cells harbouring the HCV replicon, Rubicon knockdown downregulated the expression of type 1 interferon (IFN)-related genes and upregulated HCV replication. Rubicon overexpression or administration of bafilomycin A1 or chloroquine, an inhibitor of late-stage autophagy, suppressed autophagy and activated the type 1 IFN pathway. On the other hand, Atg7 knockout suppressed early-stage autophagy and did not activate the type 1 IFN pathway. In livers of humanized liver chimeric mice, HCV infection increased Rubicon and enhanced type 1 IFN signalling. Elimination of HCV in the mice reduced the increase in Rubicon due to HCV infection. The expression levels of Rubicon and IFN-stimulated genes in chronic hepatitis C patients were higher than those in non-B, non-C hepatitis patients. HCV infection increased Rubicon and suppressed hepatocyte autophagy, leading to activation of the intracellular immune response. Rubicon induction is involved in HCV replication via activation of the intracellular immune response.

scholarly journals Paraquat Preferentially Induces Apoptosis of Late Stage Effector Lymphocyte and Impairs Memory Immune Response in Mice

2019 ◽  
Vol 16 (11) ◽  
pp. 2060 ◽  
Author(s):  
Yiming Shao ◽  
Yifan Zhao ◽  
Tingting Zhu ◽  
Fen Zhang ◽  
Xiuli Chang ◽  
...  
Keyword(s):  
Immune Response ◽  
Late Stage ◽  
Early Stage ◽  
Keyhole Limpet Hemocyanin ◽  
Primary Immune Response ◽  
Secondary Immune Response ◽  
Effector Cells ◽  
Memory Immune Response ◽  
The Impact

Paraquat (PQ) is a toxic non-selective herbicide. To date, the effect of PQ on memory immune response is still unknown. We investigated the impact of PQ on memory immune response. Adult C57BL/6 mice were subcutaneously injected with 2 mg/kg PQ, 20 mg/kg PQ or vehicle control every three days for two weeks. A single injection of keyhole limpet hemocyanin (KLH) at day four after the initial PQ treatment was used to induce a primary immune response; a second KLH challenge was performed at three months post the first KLH immunization to induce a secondary immune response. In steady state, treatment with 20 mg/kg PQ reduced the level of serum total IgG, but not that of IgM; treatment with 20 mg/kg PQ decreased the number of effector and memory lymphocytes, but not naïve or inactivated lymphocytes. During the primary immune response to KLH, treatment with 20 mg/kg PQ did not influence the proliferation of lymphocytes or expression of co-stimulatory molecules. Instead, treatment with 20 mg/kg PQ increased the apoptosis of lymphocytes at late stage, but not early stage of the primary immune response. During the secondary immune response to KLH, treatment with 20 mg/kg PQ reduced the serum anti-KLH IgG and KLH-responsive CD4 T cells and B cells. Moreover, effector or activated lymphocytes were more sensitive to PQ-induced apoptosis in vitro. Treatment with 2 mg/kg PQ did not impact memory immune response to KLH. Thus, treatment with 20 mg/kg PQ increased apoptosis of late stage effector cells to yield less memory cells and thereafter impair memory immune response, providing a novel understanding of the immunotoxicity of PQ.

scholarly journals The Real Impact of Bridging or Downstaging on Survival Outcomes after Liver Transplantation for Hepatocellular Carcinoma

Liver Cancer ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 721-733
Author(s):  
Sunyoung Lee ◽  
Kyoung Won Kim ◽  
Gi-Won Song ◽  
Jae Hyun Kwon ◽  
Shin Hwang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Early Stage ◽  
Organ Procurement ◽  
Survival Outcomes ◽  
Full Cohort ◽  
Donor Liver Transplantation ◽  
Positron Emission ◽  
The Impact

<b><i>Introduction:</i></b> There is no consensus regarding selection criteria on liver transplantation (LT) for hepatocellular carcinoma (HCC), especially for living donor liver transplantation, although emerging evidence has been found for the effectiveness of bridging or downstaging. <b><i>Objective:</i></b> We evaluated the long-term outcomes of patients who underwent LT with or without bridging or downstaging for HCC. <b><i>Methods:</i></b> This retrospective study included 896 LT recipients with HCC between June 2005 and May 2015. Recurrence-free survival (RFS), overall survival (OS), and their associated factors were evaluated. <b><i>Results:</i></b> The 5-year RFS in the full cohort of 896 patients was 82.4%, and the OS was 85.3%. In patients with initial Organ Procurement and Transplantation Network (OPTN) T1 and T2, the 5-year RFS and OS did not significantly differ between LT groups with and without bridging (all <i>p</i> ≥ 0.05). The 5-year RFS and OS of OPTN T3 patients with successful downstaging were not significantly different from those of patients with OPTN T2 with primary LT (<i>p</i> = 0.070 and <i>p</i> = 0.185), but were significantly higher than in patients with OPTN T3 with downstaging failure and initial OPTN T1 or T2 with progression (all <i>p</i> &#x3c; 0.001). In the multivariate analysis, last alpha-fetoprotein before LT ≥70 ng/mL (hazard ratio [HR]: 1.77, <i>p</i> = 0.001; HR: 1.72, <i>p</i> = 0.004), pretransplant HCC status exceeding the Milan criteria (HR: 5.12, <i>p</i> &#x3c; 0.001; HR: 3.31, <i>p</i> &#x3c; 0.001), and positron emission tomography positivity (HR: 2.57, <i>p</i> &#x3c; 0.001; HR: 2.57, <i>p</i> &#x3c; 0.001) were independent predictors for worse RFS and OS. <b><i>Conclusions:</i></b> The impact of bridging therapy on survival outcomes is limited in patients with early-stage HCC, whereas OPTN T1 or T2 with progression provides worse prognosis. OPTN T3 should undergo LT after successful downstaging, and OPTN T3 with successful downstaging allows for acceptable long-term posttransplant outcomes.

LONG-TERM ADJUSTMENT OF CAPITAL STRUCTURE: EVIDENCE FROM SINGAPORE, HONG KONG AND TAIWAN

2012 ◽  
Vol 57 (04) ◽  
pp. 1250027
Author(s):  
TERENCE TAI-LEUNG CHONG ◽  
DANIEL TAK-YAN LAW ◽  
LIN ZOU
Keyword(s):  
Hong Kong ◽  
Capital Structure ◽  
Stock Price ◽  
Pecking Order ◽  
Price Performance ◽  
Growth Opportunity ◽  
Timing Effects ◽  
The Impact ◽  
Internal Fund

This paper examines the impact of profitability, stock price performance and growth opportunity on the capital structure of firms in Singapore, Taiwan and Hong Kong. In contrast to Kayhan and Titman (2007), it is found that firms in these three Chinese-dominated economies strongly prefer debt to equity or internal fund financing. They also take advantage of stock price appreciation by issuing more shares. An adjustment model for debt ratios is estimated. The results suggest that the leverage ratios of these firms slowly adjust toward their target levels. Deviations from the target due to the pecking order and market timing effects are found to be significant.

scholarly journals Neuropathogenesis caused by Trypanosoma brucei, still an enigma to be unveiled

2021 ◽  
Vol 8 (4) ◽  
pp. 73-76
Author(s):  
Katherine Figarella
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Responses ◽  
Trypanosoma Brucei ◽  
Late Stage ◽  
Early Stage ◽  
Tropical Diseases ◽  
The Central Nervous System ◽  
The Impact ◽  
The Brain

Trypanosoma brucei is one of the protozoa parasites that can enter the brain and cause injury associated with toxic effects of parasite-derived molecules or with immune responses against infection. Other protozoa parasites with brain tropism include Toxoplasma, Plasmodium, Amoeba, and, eventually, other Trypano-somatids such as T. cruzi and Leishmania. Together, these parasites affect billions of people worldwide and are responsible for more than 500.000 deaths annually. Factors determining brain tropism, mechanisms of in-vasion as well as processes ongoing inside the brain are not well understood. But, they depend on the par-asite involved. The pathogenesis caused by T. brucei initiates locally in the area of parasite inoculation, soon trypanosomes rich the blood, and the disease enters in the so-called early stage. The pathomecha-nisms in this phase have been described, even mole-cules used to combat the disease are effective during this period. Later, the disease evolves towards a late-stage, characterized by the presence of parasites in the central nervous system (CNS), the so-called meningo-encephalitic stage. This phase of the disease has not been sufficiently examined and remains a matter of investigation. Here, I stress the importance of delve into the study of the neuropathogenesis caused by T. brucei, which will enable the identification of path-ways that may be targeted to overcome parasites that reached the CNS. Finally, I highlight the impact that the application of tools developed in the last years in the field of neuroscience will have on the study of neglect-ed tropical diseases.

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