Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

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.Subject terms: Cancer, Cancer     

Intake of arsenic from water, food composites and excretion through urine, hair from a studied population in West Bengal, India.

To evaluate the main intake source of arsenic by the villagers from arsenic-affected families in Jalangi and Domkol blocks in Mushidabad district, West Bengal-India, we determined the concentrations of arsenic in tube-well water and in food composites, mainly including vegetables and cereals collected from the surveyed families which were cultivated in that region. The daily dietary intakes of arsenic by the villagers were estimated and the excretions of arsenic through urine and hair were determined. The arsenic concentrations in hair and urine of the studied population living in mild (2.78 microg/L), moderate (30.7 microg/L) and high (118 microg/L) arsenic-affected families were 133, 1,391 and 4,713 microg/kg and 43.1, 244 and 336 microg/L, respectively. The linear regressions show good correlations between arsenic concentrations in water vs hair (r(2)=0.928, p<0.001) and water vs urine (r(2)=0.464, p<0.01). Approximately 29.4%, 58.1% and 62.1% of adult population from mild, moderate and high arsenic-affected families were suffering from arsenical skin manifestations. The mean arsenic concentrations of food composites (vegetables and cereals) in high arsenic-affected families are not significantly different from mild arsenic-affected families. The daily dietary intakes of arsenic from water and food composites of the studied population, living in high, moderate and mild arsenic-affected families were 568, 228 and 137 microg, respectively. The linear regressions show good correlations between arsenic concentrations in hair vs daily dietary intake (r(2)=0.452, p<0.001) and urine vs daily dietary intake (r(2)=0.134, p<0.001). The water for drinking contributed 6.07%, 26.7% and 58.1% of total arsenic in our study from mild, moderate and high arsenic-affected families. The result suggested that the contaminated water from high arsenic-affected families should be the main source for intake of arsenic. On contrary, the contribution of arsenic-contaminated food composites from mild and moderate arsenic-affected families might be the main source for intake of arsenic. The Food and Agriculture Organization/World Health Organization (FAO/WHO) provisional tolerable weekly intake (PTWI) values of arsenic in our study were 3.32, 5.75 and 12.9 microg/kg body weight/day from mild, moderate and high arsenic-affected families, respectively, which is higher than the recommended PTWI value of arsenic (2.1 microg/kg body weight/day).     

Presence of hepatitis B surface antigen mutant G145R DNA in the peripheral blood leukocytes of the family members of an asymptomatic carrier and evidence of its horizontal transmission

An asymptomatic carrier and all six of his family members were detected positive for HBV DNA in their peripheral blood leukocytes (PBL), by polymerase chain reaction. Direct sequencing of the amplified DNA revealed that the HBV DNA from the carrier and his wife was of subtype ayw. Interestingly, the amplified HBV DNA from the five other members of the family was found to be not only of subtype adw but also contained G to A mutation at nucleotide position 587. This indicates the presence of established vaccine escape mutant of the virus (G145R) and suggests two different sources of infection within the family. Southern blot hybridization of EcoR1 digested DNA from PBL indicated presence of HBV DNA, integrated into cellular DNA and also in the form of free viral DNA. The study not only establishes the persistence of surface mutant G145R HBV DNA, within the PBL of HBsAg negative individuals from the non-vaccinated random population, but also suggests possible horizontal transmission of the mutant among the family members although none of the family members has received immunoprophylaxis against HBV or had clinically apparent disease or any other known risk factors of HBV infection. As all of them were seronegative for HBsAg/antiHBc, the presence of G145R mutant in the PBL signaled possibility of spread of the vaccine escape mutant virus by blood transfusion, unsafe injection practices or through sexual root.     

Comparison of electrical field plethysmography with electrical impedance plethysmography

As a means for assessing cardiac function, electrical field plethysmography (EFP) has been shown to have some features quite different from electrical impedance plethysmography (EIP). Here the two techniques are compared by using the two systems simultaneously on a subject and also with independent use in different electrode configurations. The results conform with the view that EIP is related primarily to volumetric changes of the aorta, whereas EFP is affected predominantly by changes in cardiac dimensions and orientation. Because of this difference, the standard time differential formula used for EIP is not applicable for the computation of cardiac output from the EFP waveforms. An alternative method of computation based on the amplitude of the EFP waveform is suggested.     

Summation of fibre potentials and the e.m.g.-force relationship during the voluntary movement of a forearm

A linear mathematical model of the electromyogram (e.m.g.) has been developed for the biceps muscle. The number of motor units (and therefore muscle fibres) contributing to the resultant e.m.g. at any stage of movement has been found from the force analysis of elbow flexion. The depths of various motor units and the phase difference between the recruitment of any two motor units have been formulated using a spiral spread of recruitment sequence. The attenuation of individual motor-unit action potentials due to varying depths has been taken into consideration, and due regard has been taken of the length-tension diagram of a muscle while performing the force analysis. Attention has been focused on the flexion of the elbow joint, in which a method of finding the individual contribution of the biceps and brachialis muscles has been developed and applied. The results predicted by the model have been verified by experiments. The model can also be extended to the e.m.g. of other fast skeletal muscles. The conditions and limitations for such generalisations have been stated and discussed.     

Diabetes Mellitus and Heart Failure: A Consensus Statement

International Journal of Diabetes in Developing Countries -