Search

Beef meat has exceptional nutritional value that distinguishes it from other types of meat and makes it a highly valued food. However, the meat of cattle as well as other ruminants, is characterized by a more complex fatty acid profile compared to the meat of monogastric animals. This complexity is a consequence of the activity of the rumen microflora. In recent decades, changes in animal breeding, feeding practices, and modern slaughtering techniques imparted significant progress in improving beef's nutritional, sensory and market value. Different proportions of concentrated feed and roughages, as well as their types, affect the composition of intramuscular fat. Excluding genetic factors and production practices, nutrition emerges as the main factor influencing the fatty acid profile of beef meat. Today, numerous studies support the nutritional approach to modifying the fatty acid composition of beef meat by using selected feeding stuffs. Therefore, this review aims to collect and systematize data as a guide for implementing such a nutritional strategy in practice, with the health benefits of the final consumers in mind.

Introduction. The Verbands Deutscher Landwirdschaftlicher Untersuchungs und Forschungsanstalten (VDLUFA) is an association of German agronomic, analytical and scientific institutes dealing with various types of research in the field of agronomy and the development, adaptation and validation of analytical methods. This association has established an approach for determining the microbiological quality of feed based on the contents of molds, yeasts and bacteria by taking into account not only their total numbers (cfu/g), but also their potential pathogenicity. According to the degree of the potential pathogenicity, microorganisms are divided into seven groups. Based on the number of microorganisms in the seven groups, feed and feedingstuffs are classified into four categories according to microbiological quality. Materials and Methods. This method for categorization of feed is described in Methods Book III. Detailed instruction is given within the four Standard Operating Procedures (SOPs). Results and Conclusions. The VDLUFA method of assessing animal feed and feedingstuffs is a far more detailed approach that gives a more complete picture of the actual microbiological status of feed than the approach currently used in Serbia. Feed placed on the market to be used in animal nutrition should meet the criteria for classification into classes I to III, in accordance with the parameters laid down in the method. Animal feed that belongs to class IV is not suitable for animal feeding. This method could be a useful guideline in the modernization of hygienic standards for feed in Serbia in the future. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III46009]

The main reasons for wildlife forensic research are animal poaching, illegal trade, and falsified game meat products. Small trace amounts, old and degraded materials present the most common samples in revealing criminal activities in this field. This is the reason why it is crucial to use adequate and reliable methods and samples to identify animal species killed outside the hunting season or species protected by law. In this study, different endpoint PCR and real-time PCR protocols were compared in the identification of three Cervidae species (Capreolus capreolus, Cervus elaphus, Dama dama) from old and damaged material found in an enclosed area where the animals were kept. From a total of 129 samples, end point PCR provided results for 119 samples, while real-time PCR was successful in all cases. Also, we created and tested a protocol for simultaneous analyses of different types of samples, which is of great importance as when the amplification is carried out simultaneously it is more cost efficient and speeds up the process.

Different analytical techniques for the detection of mycotoxins have been developed in order to control the levels of mycotoxins in food and feed. Conventional analytical methods for mycotoxin determination are involving techniques such as thinlayer chromatography (TLC), high-performance liquid chromatography (HPLC) and gas chromatography (GC). Also, rapid methods for mycotoxin analysis have become increasingly important. Enzyme-linked immuno-sorbent assay (ELISA) is one of the most common rapid methods for determination of these natural contaminants. The aim of this study was to provide a comparison between two different methods of analysis (HPLC and ELISA) for the detection of different mycotoxins using data that originate from commercial proficiency tests. Based on the statistical evaluation of the results for both methods, in three proficiency tests for various mycotoxins (aflatoxins, ochratoxin and zearalenone), it could be concluded that both techniques can equally be used, although ELISA is considered to be the screening one. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 46009]

The quality of goat meat has recently become an important aspect in the marketing of goats in Serbia. The aim of this study was to compare some goat meat quality parameters of various races and to determine the differences between them. Goat breeds were Balkan goat and Serbian White goat, both female in the age of four years. Analysis of quality parameters: chemical composition (moisture, protein, total fat, ash,), pH value, fatty acids, amino acids, microelements content, tenderness, cooking loss and colour measurements were done. Statistically significant difference was found between the samples of two groups of goat meat (P

The objective of this work was to determine if there was a connection between stereotypical behaviour of high yielding dairy cows breeds and values of biochemical blood parameters. The investigation was carried out in august at loose-housing type of farms, in 30 heads of cattle from four groups: drying (15 to 7 days before calving), puerperium (up to 40 days after calving, early lactation (up to 120 days after calving) and late lactation (200 to 300 days after calving). Assessment of stereotypical behaviour (tongue rolling) was carried out by the method of careful observation of all the tested animals 2 to 4 hours after morning feeding. Blood samples were taken by puncture of jugular vein from 8 cows out of each animal group. In these blood samples there was determined the concentration of glucose, beta hydroxy-butyric acid (BHBA), total protein (TP), albumin, urea, total bilirubin (TBI), Ca, P, and Mg as well as AST and ALT activities. During the period up to 40 days after calving (puerperium), behavioral disorder in the form of „tongue rolling“ was found out in 4 out of 30 observed animals (13.33%). Average concentrations of all the tested blood parameters during the drying period as well as in early and late lactation were within physiological values for cattle. During puerperium there were found significantly lower values of glycaemia, proteinemia, albuminemia, uremia and magnesiemia in regard to antepartal values (p

Participation in interlaboratory comparison and proficiency testing schemes is important for laboratories to control the work quality. In this study, a sample of naturally contaminated maize was analyzed for the content of ochratoxin A (OTA) in three laboratories in Serbia. Participating laboratories used enzymatic immunoaffinity method (ELISA) for the determination of OTA and selection of the ELISA kit was free. Between-laboratory precision was acceptable as evidenced by Cochran’s C test. Moreover, z-scores for all three laboratories were z < ± 2, which is considered acceptable. Used OTA confirmation methods were thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC), with fluorescence detector. The results of different methods were comparable. [Projekat Ministarstva nauke Republike Srbije, br. TR 031071 i br. OI 172042]

The past couple of decades have provided considerable details on fungi and the toxins that they produce, as well on the mechanism of toxin action, toxicity and effects on animal and human health. But, since they are natural contaminants, their presence is often inevitable. Fusaria are widespread in all cereal-growing territories of the world, but they are especially common in our geographic area. Therefore, special attention is paid to the prevention and control, and also to the improvement of methods for their detection. Although all collected data were critical for understanding this worldwide problem, managing the impact of these toxins on the feed and food safety is still great practical challenge. There are a number of approaches that can be taken to minimize mycotoxin contamination in this chain: prevention of fungal growth and thus mycotoxin formation, strategies to reduce or eliminate mycotoxins from contaminated feedstuffs or diverting the contaminated products to low risk uses. A control program for mycotoxins from field to table should in­volve the criteria of an HACCP (Hazard Analysis Critical Control Points) approach. It requires an understanding of the important aspects of the interactions of the toxigenic fungi with crop plants, the on-farm production and harvest methods for crops, the production of livestock using grains and processed feeds, including diagnostic capabilities for mycotoxicoses, and all the way to the development of processed foods for human consumption, as well as understanding the marketing and trade channels including storage and delivery of foods to the consumer’s table. A good testing protocol for mycotoxins is necessary to manage all of the control points and in order to be able to ensure a food supply free of toxic levels of mycotoxins for the consumer. [Projekat Ministarstva nauke Republike Srbije, br. III 46009]

Chemical composition, pH value, fatty acids profile, cholesterol content, color and sensory analysis of pork meat from Duroc x Yorkshire (D x Y), Duroc x Yorkshire x wild boar (D x Y x WB) crossbreeds and wild boars (WB) was investigated. Samples for all tests were taken from m. longissimus dorsi. Chemical composition and pH value were tested by ISO methods. Fatty acid and cholesterol determination was performed by gas chromatography technique with external standard method. Color was determined instrumentally using the thristimulus colourimeter. The overall sensoric quality (appearance, texture and smell) of samples of raw meat was evaluated. In evaluation of results the scoring system was used. In chemical composition (moisture, fat, protein, ash) and pH values statistically significant difference was noted (p

This investigation was conducted in order to investigate the efficacy of the detoxifying agent Mycofix® Plus (MP) in the prevention and/or alleviation in vivo adverse effects of T-2 toxin in broilers. In addition, the adsorbing potential of MP was estimated in vitro. Mean degradation levels of T-2 toxin with MP in vitro, as measured by HPTLC, varied from 26.06 to 31.02 % and the adsorption ability was elevated in acidic environment (pH 3). In vivo trial was performed on 160 one day old "Ross" broiler chicks and lasted for 21 days. Birds were divided into 4 equal groups as follows: Group 1 - negative control; Group 2 - positive control - 2 ppm T-2 toxin; Group 3 - 2 ppm T-2 toxin+2 kg/t MP; Group 4 - 2 kg/t MP. Broilers fed the diet containing 2 mg/kg of T-2 toxin without MP developed typical T-2 toxicosis. Birds that were fed the diet containing both T-2 and MP had better performances and no oral ulcerations as the dominant sign of T-2 toxicosis were observed. Histopathological examination of tissues originating from birds fed the diet containing T-2 toxin revealed degenerative changes in the oral and small intestine mucosa, necroses of enterocytes and hepatocytes, as well as depletion of lymphocytes in the bursa Fabricii. Immunohistochemical examination also revealed negative effects of T-2 toxin on cells proliferation in intestineal and bile duct mucosa, as well as on lymphocytes from bursa Fabricii. The macroscopic and microscopic structure of the liver, intestine and bursa Fabricii of broilers fed a diet containing T-2 toxin and MP was mostly preserved. Cutaneous basophile hypersensitivity reaction was weaker in broilers fed mixtures containing 2 mg/kg T-2 toxin.

The problem of mycotoxin presence in animal feed and the consequences that arise due to this, represent a great challenge for anyone encountering them. In the chain which includes studies from prevention to treatment, a very important place and a frequent source of confusion is the process of diagnosing diseases caused by mycotoxins. The aim of this paper is to present a long experience of the team of experts at the Institute of Veterinary Medicine of Serbia in Belgrade, who follows this issue in terms of clinical manifestations of mycotoxicoses in different animal species, pathomorphological and pathohistological changes that characterize them, and laboratory analysis of feed which is the source of those biological hazards and natural contaminants. Based on the findings it could be concluded that mycotoxin contamination is common. Although these levels usually do not exceed the limits laid by the legislation, considering the cumulative effects and possible chronic exposure of animals to their harmful influence, appropriate and competent approach is necessary. Namely, even when direct losses, such as animals’ mortality, are not present, indirect losses, due to a drop of animal performances and production, as well as the occurrence of secondary infections, should not be neglected.

A 21-day-long experiment was performed on 160 one-day-old 'Ross' broiler chicks. This research was done with the aim of investigating pathomorphological changes in broilers exposed to a relatively small amount of T-2 toxin (2 ppm) and the possibility of prevention and/or alleviating adverse effects of T-2 toxin using various feed additives. Pathohistological examination showed negative consequences of T-2 toxin in all examined organs as degenerative changes developed in small intestine mucosa, enterocites and hepatocites necroses, as well as lymphocites depletion in bursa of Fabricius. Disparately from inorganic (Minazel-plus, Mz) and organic (Mycosorb, Ms) adsorbents, which did not provoke protective effects, in liver, small intestine and bursa of Fabricius of broilers who were given feed with T-2 toxin and mixed adsorbent (Mycofix-plus, Mf), mostly preserved structure of these organs could be noted.

This paper deals with the biosynthetic capacity for ochratoxin A (OTA) production by Aspergillus ochraceus E'G isolate derived from A. ochraceus CBS 108.08 strain, during 2007. Preliminary analysis of fungal potential for the production of OTA were performed according to the modified method of Filtenborg et al. (1983). Toxin production was tested in the following liquid media: (i) glucose-peptone-yeast extract broth (GPY - pH 5.6), (ii) potato-dextrose broth (PDB - pH 6.9), (iii) yeast extract-sucrose broth (YES - pH 6.5), and (iv) YES broth supplemented with 0.23 mg/l ZnSO4 x 5 H2O (YESZn - pH 6.5) after stationary and submerged cultivation. Dynamics of OTA biosynthesis was tested after the cultivation of A. ochraceus E'G on natural solid substrates, such as wet sterilized rice, corn and wheat grain. Cultivations were performed during different time periods (ranging from four days to few weeks) at different temperatures (ranging from 21°C to 30°C). The presence of OTA was determined as follows: (i) in liquid media according to the method of Balzer et al. (1978) modified by Bočarov-Stančić et al. (2003), and (ii) in the solid substrates according to the Serbian official methods for sampling and analyzing of fodder (Official Gazette of SFRY, No. 15/87). After the cultivation of A. ochraceus E'G isolate in liquid media, the highest yield of OTA (6.4 mg/l) was obtained after submerged cultivation in PDB (4 days, 128 rpm, 21-23°C). In the case of cultivation on solid substrates, the highest amount of OTA (800.0 mg/kg of dry matter) was recorded after several week long cultivation on wheat grain at 30±1°C.

All poultry is sensitive to mycotoxins. This partly depends on the type, age and production categories of poultry, their living conditions and nutritive status and partly on the type, quantity and duration of mycotoxin ingestion. The presence of mycotoxins results in significant health disorders and a decrease in production performances. This leads to considerable economic loss for the poultry industry - either direct losses, i.e. death of the poultry or the indirect ones, i.e. the decrease in body mass, number and quality of eggs, greater food conversion, and immunosuppression. Immunosuppression results in increased sensitivity to infective agents and a bad vaccinal response. Morevover, mycotoxin residues in poultry meat, eggs and products derived from them pose a threat to human health. In order to prevent and reduce the negative implications of mycotoxins in the poultry production, it is necessary to create both global and national strategies for combatting mycotoxins, advance diagnostic techniques and procedures, intensify the control of food quality, introduce new limits on the maximum amount of mycotoxins allowed in food and poultry feed used for certain species and categories of animals, and synchronise it with the European standards.

In the trial, in vitro HPTLC - High Performance Thin Layer Chomatography was used to determine the amount of 'free', i.e. unbound or non-decomposed T-2 toxin. Mean adsorption or degradation levels of T-2 toxin in examined feed aditives, in in vitro conditions, ranged from 26.06 to 34.84% and did not significantly differ among used adsorbents: inorganic (Minazel plus - Mz), organic (Mycosorb - Ms) and mixed (Micofyx - Mf). All these additives showed better adsorption ability in the acidic environment (pH3).

The influence of zearalenone on blood serum protein status and the feasibility of utilizing a modified clinoptilolite and esterified glucomannan to alleviate its harmful effects was examined in two trials, 31 and 29 days long, conducted on a total of 64 pigs (32 each) 60 days old, divided into four groups, each containing 8 pigs. Control groups (K) received noncontaminated feed, while experimental groups received feed supplemented with 3.84 mg/kg in the first trial and 5.12 mg/kg of zearalenone in the second trial. Pigs in the first experimental groups (O-I) were given feed with toxin only. Modified clinoptilolite in the amount of 0.2% and esterified glucomannan in the amount of 0.1% were introduced in contaminated feed of the second (O-II) and the third experimental groups (O-III) of both trials. With the use of contaminated feed, a declining trend of the A/G ratio was observed: decrease of albumin content and increase of globulin content on account of the _ globulin fraction. A decrease of the _ globulin fraction was detected at the same time. Total protein concentration was also lower. The application of adsorbents successfully alleviated harmful effects of the F-2 toxin on the affected biochemical parameters in blood serum.

In the course of the last decades of the twentieth century, more than 30 new diseases were determined for the first time in history. Bovine spongiform encephalopathy (BSE), or "mad cow disease" is one of them. The disease implies the subacute neurodegenerative transmission of spongiform encephalopathy and it was diagnosed and described for the first time in Great Britain in 1986. A theory has been established that BSE is spread through feedstuffs, more precisely, meat-bone flour which contains infective proteins of ruminants, and legislature has been passed throughout the world with the objective of preventing the entry of meat-bone flour into the food chain. The complete ban of the use of meat-bone flour for all farm animals (with the exception of fish flour for non-ruminants) and an adequate thermal treatment in the production of meat-bone flour (133ºC, 3 bar, 20 min) are the elements on which the European Union (EU) legislature is based. The regulations in our country include a ban on the use of meat-bone flour in cattle feedstuffs and a ban on imports of beef proteins. The implementation of this legislature throughout the world requires the corresponding analytical means. At the present time, there are several available possibilities: optic microscopy, PCR, immunoprobes, spectroscopic methods, and several others which are still being examined for use for this purpose. All the analytical methods are being applied with the objective of controlling the implementation of the current regulations, but also in order to discover possible cross contamination that could take place in factories of animal feedstuffs, during transportation, storage, or on farms, in particular when there are no separate lines for feedstuffs that contains meat-bone flour and others in which even its traces are banned. In order to secure the successful control and prevention of bovine spongiform encephalopathy in our country, as well as to secure the unhindered continuation of the integration processes with the European Union, it is necessary to create an adequate system for the monitoring of this disease, not only because of food safety as a precondition for the good health of people, but also for commercial reasons, as that is the only way to have an active role on the world market. .

It is estimated that at least 25% of grain and other cereals are today contaminated with known mycotoxins, while a large number of them are probably contaminated with as yet unidentified mycotoxins. Mycotoxins produce mold mycea, and it is believed that over 220 species have this characteristic. A large number of different mycotoxins has been identified so far, of which only a small number are of medicinal, nutritive and economic significance (aflatoxins, ochratoxins, trichotecenes, zearalenon). The listed mycotoxins present secondary metabolites, primarily the species Aspergillus, Fusarium and Penicillinum. Mycotoxicoses pose a nutritive-medical, but also a diagnostic problem, because certain mycotoxins cause changes in a number of organs. Diseases caused by mycotoxins are not contagious, they are connected with food and/or specific feed, they are similar to avitaminoses, they are not treated with antibiotics or other medicines, and they do not cause an immunological response in the organism because they are of small molecular mass so that animals are permanently protected from their effects. The content of mycotoxins in food and/or feed in practical conditions more often causes the appearance of chronic mycotoxicoses, and the effects of smaller quantities over a longer time period are the same as of bigger quantities over a short period. The early or timely establishment of the presence of mycotoxins in food and the subsequent elimination of the contaminated food from use can aleviate the negative effects, but a certain time period is required for the elimination of the resorbed quantities of mycotoxins and the disappearance of the harmful effect. That is why constant and multilevel monitoring of sanitary hygiene of feed must be practiced in production conditions in order to secure a swift and efficient reaction, as currently the only manner for the successful prevention of the harmful effects of mycotoxins.

In our country, there is present extensive, semi-intensive and intensive growing of cyprinid fish species. The quality of food is an essential prerequisite for obtaining optimal production results in fish production. Fish food is being produced as a complete pellet meal, and raw materials used are of plant, animal, mineral and vitamin origin. Out of plant feed, the most commonly used ones are corn, wheat, barley, oats, soy and others. By applying additional carbohydrate food, energetic needs of an organism are being met. In this paper, we presented the results of hygienic safety of carbohydrate feed (corn, wheat, barley) investigated in the laboratory of Veterinary Research Institute of Serbia in Belgrade within regular control, or with the aim of establishing the causes of disturbance of health status and decreased production results in the pond. During 2004 we performed microbiology and mycotoxicology investigations of the total of 43 samples, namely: 31 corn samples, 8 barley samples and 4 wheat samples. The obtained results point at a high level of mould contamination (Aspergillus, Penicillium, Fusarium, and Rhizopus) and the presence of their secondary mycotoxin metabolites (aflatoxin, ochratoxin, trichothecenes and zearalenone) in feed.

The investigation of the influence of zearalenone effects on performance of pigs and the possibility of the application of modified clinoptilolite (MC) and esterified glucomanane (EGM) in alleviating and/or prevention of harmful effects was performed by the experiment of pigs nutrition. The experiment lasted for 31 days, and the group of pigs was fed with uncontaminated feed while experimental groups were fed with feed containing 3.84 ppm of zearalenone. In pig feed of the second and third experimental group MC and EGM in the amount of 0,2 and 0,1% were added. The pigs of the control group accomplished daily growth of 0.569 kg with feed con- version of 1.793 kg. The presence of F-2 toxin in feed affected adversely production results. The addition of MC or EGM to contaminated feed improved production results, but not to the level of the control group. The obtained results point at the fact that adsorbents can only partially prevent harmful effects of F-2 toxin.

Presents an abstract for 'Immune Responses in Nucleus Basalis Magnocellularis-lesioned Rats Exposed to Chronic Isolation Stress,' by M. Popovic, N. Popovic, M. Eric-Jovicic and K. Jovanova-Nesic, published in 2000 'International Journal of Neuroscience.'

Ichthyophonosis is a disease caused by the mesomycetozoean parasite Ichthyophonus hoferi that affects a variety of fish species, including rainbow trout Oncorhynchus mykiss Walbaum. This disease is characterized by granulomatous lesions and necrosis in various organs, which can have severe impacts on the health and welfare of the fish. Ichthyophonosis has been found in several parts of the world, including Europe, and is a significant concern in the aquaculture industry and for populations of wild marine fishes. The rainbow trout is a widely cultured salmonid species in many countries, including Serbia. Although the presence of I. hoferi in rainbow trout has been reported in several countries, it has never been documented in Serbia. In this article, we report the first case of ichthyophonosis in rainbow trout in Serbia.

In ovarian and breast cancer, promoter methylation of BRCA1 or RAD51C is a promising biomarker for PARP inhibitor response, as high levels lead to homologous recombination deficiency (HRD). Yet the extent and role of such methylation in other cancers is not clear. This study comprehensively investigated promoter methylation of eight homologous recombination repair genes across 23 solid cancer types. Here, we showed that BRCA1 methylated cancers were associated with reduced gene expression, loss of heterozygosity (LOH), TP53 mutations and genomic features of HRD. We identified BRCA1 methylation in 3% of the copy-number high subtype of endometrial cancer, and as a rare event in six other cancer types, including lung squamous cell, pancreatic, bladder and stomach cancer. RAD51C promoter methylation was widespread across multiple cancer types, but HRD features were only observed for cases which contained high-level tumour methylation and LOH of RAD51C . While RAD51C methylation was frequent in stomach adenocarcinoma (6%) and low-grade glioma (2.5%), it was mostly detected at a low tumour level, suggestive of heterozygous methylation, and was associated with CpG island methylator phenotype. Our findings indicate that high-level tumour methylation of BRCA1 and RAD51C should be explored as a PARP inhibitor biomarker across multiple cancers., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Cancer.)

Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and therapy resistance. Methylation of gene promoters can have a range of impacts on cancer risk, clinical stratification and therapeutic outcomes. We provide several important examples of genes, which can be silenced or activated by promoter methylation and highlight their clinical implications. These include the mismatch DNA repair genes MLH1 and MSH2 , homologous recombination DNA repair genes BRCA1 and RAD51C , the TERT oncogene and genes within the P15/P16/RB1/E2F tumour suppressor axis. We also discuss how these methylation changes might occur in the first place - whether in the context of the CpG island methylator phenotype or constitutional DNA methylation. The choice of assay used to measure methylation can have a significant impact on interpretation of methylation states, and some examples where this can influence clinical decision-making are presented. Aberrant DNA methylation patterns in circulating tumour DNA (ctDNA) are also showing great promise in the context of non-invasive cancer detection and monitoring using liquid biopsies; however, caution must be taken in interpreting these results in cases where constitutional methylation may be present. Thus, this review aims to provide researchers and clinicians with a comprehensive summary of this broad, but important subject, illustrating the potentials and pitfalls of assessing aberrant DNA methylation in cancer., Competing Interests: CLS has served on advisory boards for Clovis Oncology, AstraZeneca, Takeda, Roche Australia, MSD, Eisai Co., has received travel support from AstraZeneca, has received in kind research support from Clovis Oncology, Roche, Beigene and Funded research support from AstraZeneca, Sierra oncology and Eisai Co. EMS has received funding for clinical trials from Clovis Oncology and TESARO (paid to her institution)., (© The Author(s), 2024.)

Background: Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease., Objectives: To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC., Design and Methods: Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 ( BRCA1/2) , four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken., Results: Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p  < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p  < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2 -mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1., Conclusion: The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy., Competing Interests: Eisai Inc. provided drug support for this study. DDB declares Consultant for Exo Therapeutics. CLS declares Advisory Boards for AstraZeneca, Clovis Oncology, Roche, Eisai Inc., Sierra Oncology, Takeda, MSD, EpsilaBio and Grant/Research support from Clovis Oncology, Eisai Inc., Sierra Oncology, Roche, Beigene, AstraZeneca and Boehringer Ingelheim. EMS declares Scientific Advisory Board for Ideaya Biosciences and DSMB role for Novartis. Other authors declare no conflicts of interest., (© The Author(s), 2023.)

BRCA1 splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs), predicted in silico to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and BRCA1 minigene modelling. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive BRCA1 exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.