Are targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma?

Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major health burden due to its increasing incidence and poor prognosis. PDAC is characterized by a low tumor mutational burden, and its molecular pathogenesis is driven by Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Response to DNA damage through homologous repair is defective in 15% of tumors. Chemotherapy using FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) or gemcitabine-nab-paclitaxel significantly improves life expectancy, but the median overall survival remains <1 year. Targeted therapies are not efficient in the overall population of patients with metastatic PDAC. Improvements in overall survival or progression-free survival, however, have been demonstrated in subgroups carrying certain mutations. Maintenance therapy with poly-ADP-ribose polymerase (PARP) inhibitors increases progression-free survival in patients with germline mutations in BRCA1/2. Sotorasib shows signs of efficacy against tumors carrying the KRAS G12C mutation, and targeted therapies may also benefit patients with KRAS-wild-type PDAC. Combining targeted therapies with chemotherapy holds promise because of potential synergistic effects. These associations, however, have not yet demonstrated clinical benefit. Checkpoint inhibitors are not effective against metastatic PDAC. Combined immunotherapies attempt to restore their efficacy but have not succeeded yet. Other immunotherapies are emerging such as therapeutic vaccines or chimeric antigen receptor (CAR) T cells, but these strategies remain to be evaluated in large trials. In the future, treatment personalization based on tumor-derived organoids could potentially further improve treatment efficiency.

Variability in disease burden and management of rheumatic fever and rheumatic heart disease in two regions of tropical Australia.

BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) contribute to Aboriginal Australian and Torres Strait Islander health disadvantage. At the time of this study, specialist ARF/RHD care in the Kimberley region of Western Australia was delivered by a broad range of providers. In contrast, in Far North Queensland (FNQ), a single-provider model was used as part of a coordinated RHD control programme. AIMS: To review ARF/RHD management in the Kimberley and FNQ to ascertain whether differing models of service delivery are associated with different disease burden and patient care. METHODS: An audit of ARF/RHD management. Classification and clinical management data were abstracted from health records, specialist letters, echocardiograms and regional registers using a standardised data collection tool. RESULTS: Four hundred and seven patients were identified, with 99% being Aboriginal and/or Torres Strait Islanders. ARF without RHD was seen in 0.4% of Aboriginal and/or Torres Strait Islander residents and RHD in 1.1%. The prevalence of RHD was similar in both regions but with more severe disease in the Kimberley. More FNQ RHD patients had specialist review within recommended time frames (67% vs 45%, χ(2) , P < 0.001). Of patients recommended benzathine penicillin secondary prophylaxis, 17.7% received ≥80% of scheduled doses in the preceding 12 months. Prescription and delivery of secondary prophylaxis was greater in FNQ. CONCLUSIONS: FNQ's single-provider model of specialist care and centralised RHD control programme were associated with improved patient care and may partly account for the fewer cases of severe disease and reduced surgical procedures and other interventions observed in this region.

Acute rheumatic fever and rheumatic heart disease--priorities in prevention, diagnosis and management. A report of the CSANZ Indigenous Cardiovascular Health Conference, Alice Springs 2011.

Three priority areas in the prevention, diagnosis and management of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) were identified and discussed in detail: 1. Echocardiography and screening/diagnosis of RHD ­ Given the existing uncertainty it remains premature to advocate for or to incorporate echocardiographic screening for RHD into Australian clinical practice. Further research is currently being undertaken to evaluate the potential for echocardiography screening. 2. Secondary prophylaxis ­ Secondary prophylaxis (long acting benzathine penicillin injections) must be seen as a priority. Systems-based approaches are necessary with a focus on the development and evaluation of primary health care-based or led strategies incorporating effective health information management systems. Better/novel systems of delivery of prophylactic medications should be investigated. 3. Management of advanced RHD ­ National centres of excellence for the diagnosis, assessment and surgical management of RHD are required. Early referral for surgical input is necessary with multidisciplinary care and team-based decision making that includes patient, family, and local health providers. There is a need for a national RHD surgical register and research strategy for the assessment, intervention and long-term outcome of surgery and other interventions for RHD.

Community-acquired pneumonia in the central desert and north-western tropics of Australia.

BACKGROUND: Community-acquired pneumonia (CAP) results in significant morbidity in central and north-western Australia. However, the nature, management and outcome of CAP are poorly documented. The aim of the study was to describe CAP in the Kimberley and Central Desert regions of Australia. METHODS: Prospective and retrospective cohort studies of inpatient management of adults with CAP at Alice Springs Hospital and six Kimberley hospitals were carried out. We documented demographic data, comorbidities, investigations, causes, CAP severity, outcome and concordance between prescribed and protocol-recommended antibiotics. RESULTS: Two hundred and ninety-three subjects were included. Aboriginal Australians were overrepresented (relative risk 8.1). Patients were notably younger (median age 44.5 years) and disease severity lower than in urban Australian settings. Two patients died within 30 days of admission compared with expected mortality based on Pneumonia Severity Index predictions of seven deaths (chi(2), P= 0.09). Disease severity and outcome did not differ between regions. Management differences were identified, including significantly more investigations, higher rates of critical care and broader antibiotic cover in Central Australia compared with the Kimberley. Sputum culture results showed Gram-negative organisms in both regions. However, Streptococcus pneumoniae was the most frequent organism isolated in the Kimberley and Haemophilus influenzae in Central Australia. CONCLUSION: CAP in this setting is an Aboriginal health issue. The low mortality observed and results of microbiology investigations support the use of existing antibiotic protocols. Larger studies investigating CAP aetiology are warranted. Addressing social and environmental disadvantage remains the key factors in dealing with the burden of CAP in this setting.

Efficacy of particle-based DNA delivery for vaccination of sheep against FMDV.

As an alternative strategy to classical inactivated viral vaccine against FMDV, naked DNA vaccine is attractive because of safety, flexibility and low cost. However DNA vaccination is usually poorly efficient in target species. Indeed we found that naked DNA plasmids encoding for P1-2A3C3D and GM-CSF proteins did not induce any detectable immunity against FMDV in sheep. Interestingly, we demonstrate herein that formulations of DNA on poly(D,L-lactide-co-glycolide) (PLG) or in lipofectin triggered divergent types of immune responses: PLG stimulated a T cell response and could elicit significant neutralising antibody titers, whereas lipofectin generated even higher antibody titers but no significant T cell response. The DNA/PLG regimen used in five sheep protected against clinical symptoms and viraemia and prevented the carrier state in four of them. Thus formulated DNA can be remarkably efficient against FMDV in a ruminant species that is usually refractory to DNA vaccination.

A cell signal from the coral Plesiastrea versipora reduces starch synthesis in its symbiotic alga, Symbiodinium sp.

We have previously shown that the coral cell signal, host release factor (HRF) from the scleractinian coral Plesiastrea versipora (Lamarck) stimulates the release of glycerol from its symbiotic dinoflagellate, Symbiodinium sp. Glycerol is a precursor for algal triacylglycerol (TG) and starch, and we have previously observed that HRF reduces the amount of newly synthesized TG in Symbiodinium sp. We have now examined the effect of P. versipora HRF on starch synthesis in isolated Symbiodinium. HRF had no effect on starch synthesis after 2 h photosynthesis (16.3+/-3.0 microg starch per 10(6) algae) compared with algae in seawater (13.9+/-1.2 microg starch per 10(6) algae). However, after 4 h incubation in HRF, there was a reduction (0-76%), in the amount of newly synthesized starch which was correlated with the amount of HRF (10-76 microg/ml). Reducing algal synthesis of both TG and starch in parallel with stimulating glycerol release may provide a mechanism to regulate the population density of intracellular symbiotic algae while still ensuring the transfer of photosynthetically fixed carbon to the animal host in the form of glycerol.

Expression of a foot-and-mouth disease virus immunodominant epitope by a filamentous bacteriophage vector.

We described the construction of a recombinant filamentous phage displaying on its surface the immunodominant site of VP1 protein of foot-and-mouth disease virus (FMDV). The coding sequence was inserted at the amino-terminus of the major coat protein pVIII via a spacer. The hybrid phage proved to be antigenic as it was recognized by polyclonal and monoclonal anti FMDV sera. In two experiments involving immunisation of guinea-pigs with the recombinant phage, a low antibody response was generated. This suggests a possible role for phage displayed peptides in inducing anti FMDV immunity and the possibility of further development is discussed.

Residual foot-and-mouth disease virus antibodies in French cattle and sheep six years after the vaccination ban.

A serological survey was carried out on French cattle to establish a reference pattern of residual vaccine antibodies and non-specific reactions against the foot-and-mouth disease virus 6 years after the ban on vaccination and in the absence of any foot-and-mouth disease outbreak. Most of the multi-vaccinated cattle still displayed high titres of antibodies and up to 50% of those which had received a single injection still had antibodies. Non-specific reactors were also recorded among animals born during and after 1991. Most of them displayed low titres close to the threshold. Sheep were also tested and, as for cattle, 4.6% of non-specific reactors were recorded, with titres close to the threshold for two-thirds of them. As part of these animals have been resampled and retested, sera revealed negative confirming that these animals are true non-specific reactors. Serological testing as a mean of FMD control should take these facts into account.

Exposure of in vitro-produced bovine embryos to foot-and-mouth disease virus.

The aim of this study was to investigate whether foot and mouth disease virus (FMDV) interacts with in vitro produced (IVP) bovine embryos. One milliliter of a suspension of FMDV (2 x 10(7) TCID50/mL) was added to several batches of these embryos 7 d after in vitro fertilization, by which time they had either developed to the morula/blastocyst stage (n = 256) or degenerated (n = 260). Six experiments were performed in which developed or degenerated batches of embryos were incubated with FMDV for periods of 1 h (3), 2 h (2) or 4h (1). After this, the embryos were washed 10 times according to the International Embryo Transfer Society (IETS), then pooled and ground up to form a suspension, and assayed on cell cultures for FMDV. The cell cultures were observed daily for cytopathic effects for 3 d post exposure. In addition to the cell culture method, the polymerase chain reaction (PCR) technique was used to assay for the presence of the virus in the washing fluids. Assays for FMDV were also conducted on the first and second wash and on the pooled sample constituting the eight, ninth and tenth wash. With the exception of the second wash from a batch of embryos exposed to FMDV for 2 h, all samples of the first and second wash produced FMDV cytopathic effects, but none occurred with the pooled samples of the 8th, 9th and 10th wash. FMDV was also isolated from all but 1 of the batches of embryos after 1 h of incubation, from 1 of 4 batches after 2 h of incubation and from all batches after 4 h incubation. By contrast, the presence of virus could not be demonstrated by PCR based on the technique used here. These results show that 7 d old IVP bovine embryos can retain FMDV after washing, unlike in vivo-derived embryos, which do not appear to carry risks of FMDV transmission when washed according to IETS recommendations. Stricter controls are, therefore, necessary when using IVP embryos from cattle in a non-FMD-free zone in domestic or international trade.

[Infectious pathology of Canidae and Felidae in zoological parks]. / Pathologie infectieuse des Canidés et Félidés des parcs zoologiques.

The Canidae (36 species) and Felidae (34-37 species) are two families of carnivores represented by numerous exotic species in zoos or wildlife reserves. To some extent, the diseases of these species are similar to those of dogs and cats, and are therefore relatively well known. However, there are differences in sensitivity to infectious agents, treatments and vaccines. Canidae and Felidae may also act as carriers or even vectors of zoonoses, such as leptospirosis, rabies, salmonellosis, toxoplasmosis and tuberculosis. Due to their behaviour patterns and morphological adaptations, these species are capable of transmitting various opportunistic infections by biting or scratching. These characteristics mean that Canidae and Felidae are difficult to keep in captivity, and require special health precautions, particularly protection from contact with stray carnivores.

Gene organization in the UL region and inverted repeats of the canine herpesvirus genome.

Restriction mapping and the determination of scattered nucleotide sequences have permitted a description of the global structure and evolutionary affinities of the canine herpesvirus (CHV) genome. The global structure closely resembles that of the totally sequenced genomes of varicella-zoster virus and equine herpesvirus 1 (EHV-1) in having a 37 bp inverted repeat flanking a long unique region (UL) of approximately 100,000 bp, and a 10,100-10,700 bp inverted repeat flanking a short unique region (U8) of roughly 7,400-8,600 bp. On the basis of the sequences obtained, 35 homologues to previously identified herpesvirus gene products were found in UL and the major inverted repeat, and the level of the similarities indicated that CHV belongs to the genus Varicellovirus. Within the genus, CHV appears to be most closely related to EHV-1, pseudorabies virus and feline herpesvirus. Surprisingly, genes for both subunits of the viral ribonucleotide reductase were found to be missing from their equivalent place in other herpesvirus genomes. Either they have been translocated to another position in the CHV genome or, we think more likely, they have been lost.

Sequence of the canine herpesvirus thymidine kinase gene: taxon-preferred amino acid residues in the alphaherpesviral thymidine kinases.

Multiple sequence alignments of evolutionarily related proteins are finding increasing use as indicators of critical amino acid residues necessary for structural stability or involved in functional domains responsible for catalytic activities. In the past, a number of alignments have provided such information for the herpesviral thymidine kinases, for which three-dimensional structures are not yet available. We have sequenced the thymidine kinase gene of a canine herpesvirus, and with a multiple alignment have identified amino acids preferentially conserved in either of two taxons, the genera Varicellovirus and Simplexvirus, of the subfamily Alphaherpesvirinae. Since some regions of the thymidine kinases show otherwise elevated levels of substitutional tolerance, these conserved amino acids are candidates for critical residues which have become fixed through selection during the evolutionary divergence of these enzymes. Several pairs with distinctive patterns of distribution among the various viruses occur in or near highly conserved sequence motifs previously proposed to form the catalytic site, and we speculate that they may represent interacting, co-ordinately variable residues.

Partial DNA cloning and sequencing of a canine parvovirus vaccine strain: application of nucleic acid hybridization to the diagnosis of canine parvovirus disease.

The cloning and sequencing of an Eco RI-PstI fragment derived from the replicative form of a canine parvovirus (CPV) vaccine strain are reported. The variability of the 5' end of NS 1 protein gene in the genome is confirmed by comparison with previously determined DNA sequences. A 15 nucleotide deletion was also observed in this vaccine strain. In order to improve CPV diagnosis, radioactively labelled RNA or DNA and biotin labelled DNA obtained by random priming of the recombinant plasmid were used as probes mainly on gut or stool samples from naturally infected dogs. Results of filter hybridization correlated well with histopathological diagnosis of parvovirus infection and with hemagglutination tests performed on dog faeces. We propose that nucleic acid hybridization may be an alternative diagnostic method to ascertain the presence of CPV, especially in frozen samples.

Variations of cochlear microphonic potential after sectioning efferent fibers to the cochlea.

Cochlear microphonic (CM) potentials were recorded, in guinea pig, with differential electrodes before and after sectioning the medial efferent innervation at the level of the brainstem. Sectioning the crossed part of the medial efferent innervation did not change the CM whatever the frequency or level of stimulation used. Sectioning the medial--crossed and uncrossed--efferent fibers diminished CM amplitude at frequencies above 2 kHz. Thus, the ipsilateral medial efferent tract seems to be involved, through a tonic action, in controlling outer hair cell micromechanics.

[New data on the physiology of the olivo-cochlear efferent systems]. / Nouvelles données sur la physiologie des systèmes efférents olivocochléaires.

The medial part of the olivocochlear efferent tract seems to be involved in two distinct phenomena. The crossed part is involved in the masking function and the uncrossed one in the control, through a tonic action, of the cochlear micromechanics.

Efferent tracts and cochlear frequency selectivity.

The cochlear innervation of guinea pigs was sectioned medially in a rostrocaudal direction at the level of the floor of the fourth ventricle, to study the effects of efferent pathways on cochlear microphonic (CM) suppression, the compound action potential (CAP) masking phenomenon, the input-output CAP function, and cochlear frequency selectivity estimated with tuning curves of single auditory nerve fibers. Sectioning reduced CM suppression without having any effect on absolute CM amplitude; it also reduced CAP masking. The input-output CAP function was not changed at intensities below 75 dB, and the single-unit tuning curves recorded before and after nerve sectioning were unaffected. Thus, the crossed efferent tracts (i.e., mainly the medial system) seems to be involved in the masking function itself, rather than one of the mechanisms responsible for high frequency cochlear selectivity.

Effects of section of the medial efferent tracts (crossed and uncrossed) on cochlear frequency selectivity.

The cochlear innervation of guinea pigs was sectioned midway between the midline and the external side of the cochlear nucleus, in a rostrocaudal direction at the level of the floor of the fourth ventricle, to study the effects of medial efferent pathways on cochlear frequency selectivity estimated with tuning curves of single auditory nerve fibers. Single-unit tuning curves were affected by this type of efferent sectioning. Thus, the ipsi-lateral efferent system seems to be involved, through a tonic action, in the mechanisms responsible for high frequency cochlea selectivity.

A comparison of compound action potential and cochlear microphonic two-tone suppression in the guinea pig.

Cochlear microphonics (CM) and compound action potentials (AP) were recorded simultaneously with differential electrodes in the basal turn of the guinea pig cochlea. When CM two-tone suppression (2TS) curves were compared to AP simultaneous masking curves, good correspondence was observed between CM and AP suppression effects. The relationship between the 10 dB bandwidths of CM and AP 2TS curves remained constant for each animal despite differences between animals resulting from natural variations. Under pathological conditions (acute cochlear hypoxia) both CM and AP two-tone suppression effects were greatly reduced or disappeared. These results can be taken as evidence that CM suppression and AP suppression are the products of a common underlying mechanism.