Antiviral properties of chemical inhibitors of cellular anti-apoptotic Bcl-2 proteins

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.</p

Diagnosis and surgical treatment of suspicious nonpalpable breast lesions and early breast cancer

Abstract The purposes of the present research were to evaluate (1) the value of ultrasonographically guided fine-needle aspiration biopsy (US-FNAB) in nonpalpable suspicious breast lesions, (2) the preoperative use of methylene blue staining in nonpalpable galactographically suspicious breast lesions, (3) the determinants of positive histologic margins and residual cancer in wire-guided biopsy (WGB) of nonpalpable breast cancer and in lumpectomy for early breast cancer and the determinants of positive radiologic margins and the correlation between radiologic and histologic margins and residual disease in WGB of nonpalpable breast cancer, (4) the assessment of lumpectomy margins by touch preparation cytology in early breast cancer, and (5) the cosmetic outcome of WGB performed for benign breast lesions. The sensitivity and specificity of US-FNAB in 90 nonpalpable breast lesions were 84% and 93%, respectively. Preoperative methylene blue staining was successful in 22 out of 30 (73%) cases, making subsequent selective minimal volume microdochectomy easy to perform. Multivariate analysis of 21 prospectively evaluated variables was done after 71 WGBs of nonpalpable breast cancer followed by 54 re-excisions. Large mammographic lesions had more often positive radiologic margins. Multifocality, large pathologic size and superficial excision were related to positive histologic margins and multifocality to residual disease in re-excisions. The sensitivity and specificity of specimen radiography for predicting histologic margins were 38% and 81% and those for residual disease 27% and 79%, respectively. The corresponding figures for histologic margins in predicting residual disease were 85% and 59%, respectively. In a prospective series of 55 consecutive lumpectomies for early breast cancer, positive histologic margins were found more often in the presence of intraductal cancer and if the pathologic size of the index tumor was large. Residual disease was found in 38% of the cases with positive and in 15% of the cases with negative histologic margins. A multifocal and nonpalpable index tumor predicted residual cancer in 34 re-excision specimens. The sensitivity and specificity of touch preparation cytology in predicting histologic margins were 38% and 85%, respectively. In WGB, the overall cosmesis 6 months after surgery was satisfactory in 75 % of the 101 prospectively evaluated patients with benign proven lesions. Cosmesis was poorer after deep excisions and complications. The results indicate that US-FNAB is a useful tool in evaluating nonpalpable suspicious breast lesions. Preoperative methylene blue staining crucially facilitates selective minimal volume microdochectomy in three-quarters of cases. To obtain free margins in WGB, mammographically and pathologically large lesions should be removed with wider excisions extending down to the fascia. However, radiologic margins in WGB and histologic margins both in WGB and in lumpectomy for early breast cancer may be misleading. Re-excision of the biopsy site of multifocal tumors after WGB and lumpectomy should be considered. This is also important after superficial excision in WGB due to the considerable risk of residual disease. Touch preparation cytology cannot be recommended for the assessment of margins in lumpectomy specimens of early breast cancer. Cosmetic outcome after WGB of benign breast lesions is satisfactory in 75 % of cases. Deep excisions and complications endanger the cosmetic outcome. Preoperative biopsy and tumor localization methods have proven their utility; nevertheless, free margins are still difficult to obtain and to evaluate accurately. The surgeon may often be forced to choose between free margins and an acceptable cosmetic outcome

International aspects of growth management in eHealth service start-ups

Abstract Stages of growth theory provide little or no evidence regarding international aspects of growth management. Moreover, international entrepreneurship research and the international new venture approach view the growth of start-ups through the perspective of internationalisation, without a special growth management focus. There is a need for research which integrates both aspects. The start-up stage is the most critical period for the survival of a company, as decisions made during this time have a decisive influence on its success, if not survival. Digitalisation is revolutionising international business, and healthcare delivery is no exception. It provides business opportunities, even globally, for innovative start-ups. The aim of this chapter is to clarify international aspects of growth management in eHealth service start-ups. Utilising critical incident techniques and semi-structured interviews in the data collection, managerial priorities are analysed in five case companies in Finland, Sweden and the U.S. The findings demonstrate that international aspects are inseparable from the growth management of international eHealth start-ups. The key management priority areas related to internalisation are focus, strategic management and service development and delivery

Evolution of pancreatic surgery over time and effects of centralization:a single-center retrospective cohort study

Abstract Background: Short-term outcomes of pancreatic surgery have improved globally during the last two decades. Long-term survival of resectable pancreatic ductal adenocarcinoma (PDAC) has also shown slight improvement. We describe a cohort of 566 consecutive pancreatectomies performed at a Northern Finnish tertiary center. We analyze the trends in short-term outcomes of all-cause pancreatic surgery and long-term survival of PDAC patients. Methods: All pancreatic resections performed at the Oulu University Hospital during years 2000–2020 were included. Patient data was analyzed in four time periods (2000–2005, 2006–2010, 2011–2015 and 2016–2020). Clinicopathological parameters of patients and tumors, complication data and short-term mortality were recorded for all patients and compared between time quartiles. Long-term survival and administration rates of neo-, and/or adjuvant therapy of PDAC patients were analyzed. Results: A total of 566 pancreatectomies were performed during the study period: 359 (63%) pancreatoduodenectomies (PDs), 130 (23.0%) open left pancreatectomies (LPs), 45 (8.0%) laparoscopic LPs, 26 (5.1%) total pancreatectomies (TPs), and 6 (1.1%) enucleations. Median age of patients was 63 [57–71] years, and 49% [267] of patients were men. Number of pancreatectomies per time period increased from 67 in 2000–2005 to 266 in 2016–2020. American Society of Anesthesiologists (ASA) Physical Classification III patients and T3 tumors were more frequently operated on in later time periods. Complication rates remained at constant low levels throughout the study period, but reoperation rate increased from 9.4% in 2000–2010 to 16.2% in 2011–2020. Short-term (90-day) mortality after pancreatectomy decreased from 3.1% to 0.74%, while 5-year survival improved from 14.3% in 2006–2011 to 21.4% in 2011–2015. Resection rate of diagnosed PDAC cases, as reported by the Finnish Cancer Registry (FCR) for the catchment area, increased from 3.2% to 14.9% over the study period. Conclusions: The hospital volume of pancreatectomies has increased substantially, while complications and postoperative mortality have remained at acceptable levels. Long-term survival and resection rate of PDAC patients showed notable improvement over two decades