Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5-10% of all human cancers, although this ...frequency increases to 10-30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.
The history of the Black Sea as a source of Mediterranean slaves
stretches from ancient Greek colonies to human trafficking networks
in the present day. At its height during the fourteenth and early
...fifteenth centuries, the Black Sea slave trade was not the sole
source of Mediterranean slaves; Genoese, Venetian, and Egyptian
merchants bought captives taken in conflicts throughout the region,
from North Africa, sub-Saharan Africa, the Balkans, and the Aegean
Sea. Yet the trade in Black Sea slaves provided merchants with
profit and prestige; states with military recruits, tax revenue,
and diplomatic influence; and households with the service of women,
men, and children.
Even though Genoa, Venice, and the Mamluk sultanate of Egypt and
Greater Syria were the three most important strands in the web of
the Black Sea slave trade, they have rarely been studied together.
Examining Latin and Arabic sources in tandem, Hannah Barker shows
that Christian and Muslim inhabitants of the Mediterranean shared a
set of assumptions and practices that amounted to a common culture
of slavery. Indeed, the Genoese, Venetian, and Mamluk slave trades
were thoroughly entangled, with wide-ranging effects. Genoese and
Venetian disruption of the Mamluk trade led to reprisals against
Italian merchants living in Mamluk cities, while their
participation in the trade led to scathing criticism by supporters
of the crusade movement who demanded commercial powers use their
leverage to weaken the force of Islam.
Reading notarial registers, tax records, law, merchants'
accounts, travelers' tales and letters, sermons, slave-buying
manuals, and literary works as well as treaties governing the slave
trade and crusade propaganda, Barker gives a rich picture of the
context in which merchants traded and enslaved people met their
fate.
This study argues that businesswomen were central to urban society and to the operation and development of commerce in the late eighteenth and early nineteenth centuries. It presents a rich and ...complicated picture of lower-middling life and female enterprise in three northern English towns: Manchester, Leeds, and Sheffield. The stories told by a wide range of sources - including trade directories, newspaper advertisements, court records, correspondence, and diaries - demonstrate the very differing fortunes and levels of independence that individual businesswomen enjoyed. Yet, as a group, their involvement in the economic life of towns and, in particular, the manner in which they exploited and facilitated commercial development, force us to reassess our understanding of both gender relations and urban culture in late Georgian England. In contrast to the traditional historical consensus that the independent woman of business during this period - particularly those engaged in occupations deemed 'unfeminine' - was insignificant and no more than an oddity, businesswomen are presented here not as footnotes to the main narrative, but as central characters in a story of unprecedented social and economic transformation. The book reveals a complex picture of female participation in business. It shows that factors traditionally thought to discriminate against women's commercial activity - particularly property laws and ideas about gender and respectability - did have significant impacts upon female enterprise. Yet it is also evident that women were not automatically economically or socially marginalized as a result. The woman of business might be subject to various constraints, but at the same time, she could be blessed with a number of freedoms, and a degree of independence that set her apart from most other women - and many men - in late Georgian society. Available in OSO: http://www.oxfordscholarship.com/oso/public/content/history/9780199299713/toc.html
The history of the Black Sea as a source of Mediterranean slaves stretches from ancient Greek colonies to human trafficking networks in the present day. At its height during the fourteenth and early ...fifteenth centuries, the Black Sea slave trade was not the sole source of Mediterranean slaves; Genoese, Venetian, and Egyptian merchants bought captives taken in conflicts throughout the region, from North Africa, sub-Saharan Africa, the Balkans, and the Aegean Sea. Yet the trade in Black Sea slaves provided merchants with profit and prestige; states with military recruits, tax revenue, and diplomatic influence; and households with the service of women, men, and children.Even though Genoa, Venice, and the Mamluk sultanate of Egypt and Greater Syria were the three most important strands in the web of the Black Sea slave trade, they have rarely been studied together. Examining Latin and Arabic sources in tandem, Hannah Barker shows that Christian and Muslim inhabitants of the Mediterranean shared a set of assumptions and practices that amounted to a common culture of slavery. Indeed, the Genoese, Venetian, and Mamluk slave trades were thoroughly entangled, with wide-ranging effects. Genoese and Venetian disruption of the Mamluk trade led to reprisals against Italian merchants living in Mamluk cities, while their participation in the trade led to scathing criticism by supporters of the crusade movement who demanded commercial powers use their leverage to weaken the force of Islam.Reading notarial registers, tax records, law, merchants' accounts, travelers' tales and letters, sermons, slave-buying manuals, and literary works as well as treaties governing the slave trade and crusade propaganda, Barker gives a rich picture of the context in which merchants traded and enslaved people met their fate.
Addressing cigarette and e-cigarette use in China is key to reducing the global tobacco epidemic. Marketing exposure is one causal factor for adolescent smoking and e-cigarette use. Currently, China ...restricts cigarette and e-cigarette ads in public places and online; however, there may not be full policy compliance. We collected real-time data in the natural environment to estimate how much and where Chinese adolescents - a group susceptible to smoking and e-cigarette use - are exposed to cigarette and e-cigarette marketing to inform policy responses.
In June 2022, we conducted a seven-day ecological momentary assessment (EMA) study with 15-16-year-olds (n=96) across eight Chinese cities. Participants completed up to 42 EMA surveys (6 per day), sent at random intervals outside of school hours. In each survey, participants reported whether they saw (1) displays and (2) ads in the past hour (none, cigarette, e-cigarette, both) in the past hour. We also captured the source of cigarette/e-cigarette ad exposure.
Most participants were exposed to cigarette and/or e-cigarette displays (89.6%) or ads (79.2%) over the seven days. On average, participants reported past-hour exposure to displays 12.7 times and past-hour exposure to ads 10.8 times over the week. The most common sources of cigarette ads were public places (e.g., kiosks, supermarkets); the most common sources of e-cigarette ad exposure were social media/internet or e-cigarette stores.
Findings highlight the need to enhance enforcement of restrictions on cigarette and e-cigarette ads in public places and online in China and extend restrictions to ban displays.
Marketing exposure is a causal factor in youth smoking and e-cigarette use. We used ecological momentary assessments to estimate cigarette and e-cigarette display and ad exposure among Chinese adolescents. On average, participants reported past-hour exposure to cigarette and/or e-cigarette displays 13 times and past-hour exposure to cigarette and/or e-cigarette ads 11 times over one week. Most saw ads in public places and online. Results suggest strengthening implementation of China's ban on cigarette and e-cigarette ads in public places and online and banning product displays. These are policy responses that can contribute to reducing adolescent cigarette and e-cigarette uptake in China.
The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase ...inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the
kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these
SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated
Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the
p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.
Adolescents are uniquely vulnerable to nicotine addiction, and smoking is common among male adolescents in China. Although China implemented a ban on cigarette and e-cigarette advertising in public ...places, Chinese youth remain exposed to this marketing, which may contribute to future use.
From December 2021 to January 2022, we conducted 20 online focus group discussions with 119 adolescents in 10 Chinese cities to explore sources of tobacco marketing exposure, defined as exposure to cigarette and e-cigarette ads and product displays, and what features made marketing attractive.
All groups discussed exposure to tobacco ads/displays in public places, including locations near their home or school. Nearly all groups discussed that exposure to online tobacco ads was common, particularly exposure to e-cigarette commercial ads and posts made by classmates or friends selling e-cigarettes. Most groups identified how eye-catching colors, imagery, product packaging, and price promotions featured in e-cigarette ads/displays attracted their attention.
Results suggest Chinese adolescents are exposed to cigarette and e-cigarette ads and displays, many of which are placed in youth-friendly locations and contain youth-appealing features.
Only a handful of studies have examined the influence of cigarette and e-cigarette advertising on youth in the context of China. Prior research has established the relationship between youth exposure to tobacco marketing and increased susceptibility to future use. Our findings emphasize the importance of effectively enforcing and expanding restrictions on cigarette and e-cigarette marketing in order to protect youth from exposure and future smoking/vaping initiation.
Raising cigarette prices, increasing graphic health warning label (HWL) coverage and requiring plain packaging could reduce cigarette smoking in Vietnam. This discrete choice experiment estimates the ...potential impact of these policies on smoking behaviour.
In February-May 2022, we conducted a phone-based, cross-sectional survey of 1494 Vietnamese adults who smoke. Participants were randomly assigned to view four individual cigarette pack images, varied on price (15 000 (
); 20 000; 30 000 or 40 000 Vietnamese dong (VND)) and packaging (branded pack with 50% graphic HWL (
); branded pack with 85% graphic HWL; plain pack with 50% graphic HWL or branded pack without HWL). Participants responded if they would quit or continue smoking if they could only purchase the pack shown. We used binomial logistic regressions to estimate the relative risk (RR) of price and packaging on hypothetical quitting.
Participants were more likely to report they would quit when presented with 30 000 VND (RR 1.20, 95% CI 1.07 to 1.35) and 40 000 VND packs (RR 1.40, 95% CI 1.23 to 1.58) vs the 15 000 VND pack. Participants were also more likely to report they would quit when shown the branded pack with 85% HWL (RR 1.30, 95% CI 1.18 to 1.42) and plain pack with 50% HWL (RR 1.34, 95% CI 1.21 to 1.49) vs the branded pack with 50% HWL coverage. Participants had significantly lower quit likelihood (RR 0.41, 95% CI 0.35 to 0.48) when shown the branded pack without a HWL.
Results suggest raising cigarette prices to at least 30 000 VND, implementing larger graphic HWLs or plain packaging could decrease smoking rates in Vietnam.
When, how, and why did the Black Death reach Europe? Historians have relied on Gabriele de’ Mussi’s account of Tatars catapulting plague-infested bodies into the besieged city of Caffa on the Crimean ...Peninsula. Yet Mussi spent the 1340s in Piacenza; he had no direct knowledge of events in Caffa. Sources by people present in the Black Sea during the Second Pandemic, including Genoese colonial administrators, Venetian diplomats, Byzantine chroniclers, and Mamluk merchants, offer a different perspective. They show that the Venetian community at Tana played an important role in plague transmission; that it took over a year (from spring 1346 to autumn 1347) for plague to cross the Black Sea to Constantinople; that people crossed the Black Sea in 1346 but commodities did not because of a series of trade embargoes; that grain was one of the most important Black Sea commodities in both volume and strategic value; and therefore that the embargoes of 1346 delayed plague transmission by temporarily halting the movement of grain with its accompanying rats, fleas, and bacteria. When Venice, Genoa, and the Golden Horde made peace and lifted their embargoes in 1347, both the grain trade and the spread of plague resumed.
Small businesses were at the heart of the economic growth and social transformation that characterized the Industrial Revolution in Britain. In towns across north-west England, shops and workshops ...dominated the streetscape, and helped to satisfy an increasing desire for consumer goods. Yet, despite their significance, we know surprisingly little about these firms and the people who ran them, for, while those engaged in craft-based manufacturing, retailing, and allied trades constituted a significant proportion of the urban population, they have been generally overlooked by historians. Instead, our view of the world of business is more usually taken up by narratives of particularly successful firms, and especially those involved in new modes of production. By examining some of the forgotten businesses of the Industrial Revolution, and the men and women who worked in them, this book presents a largely unfamiliar commercial world. Its approach, which spans economic, social, and cultural history, as well as encompassing business history and the histories of the emotions, space, and material culture, alongside studies of personal testimony, testatory practice, and property ownership, tests current understandings of gender, work, family, class, and power in the late eighteenth and early nineteenth centuries. It provides us with new insights into the lives of ordinary men and women in trade, whose relatively mundane lives are easily overlooked, but who were central to the story of a pivotal period in British history.
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