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CAR T cell-based therapies have revolutionized the treatment of hematological malignancies such as leukemia and lymphoma within the last years. In contrast to the success in hematological cancers, the treatment of solid tumors with CAR T cells is still a major challenge in the field and attempts to overcome these hurdles have not been successful yet. Radiation therapy is used for management of various malignancies for decades and its therapeutic role ranges from local therapy to a priming agent in cancer immunotherapy. Combinations of radiation with immune checkpoint inhibitors have already proven successful in clinical trials. Therefore, a combination of radiation therapy may have the potential to overcome the current limitations of CAR T cell therapy in solid tumor entities. So far, only limited research was conducted in the area of CAR T cells and radiation. In this review we will discuss the potential and risks of such a combination in the treatment of cancer patients.

Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic “driver” mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness. The role of mutations within long noncoding RNAs (lncRNAs) exons on tumour cell fitness remains to be explored. Here, the authors investigate the landscape of driver lncRNAs in primary and metastatic samples and validate the functional significance of single nucleotide variants in the NEAT1 oncogene in vitro and in vivo.

Vaccination uptake is essential to controlling the ongoing COVID-19 pandemic. Healthcare workers (HCWs) play a critical role in receiving, recommending and delivering COVID-19 vaccination. Understanding the specific influences on each behaviour enables the development of targeted and tailored interventions to improve vaccination uptake. This paper presents a qualitative synthesis of HCWs’ individual and context barriers and drivers to these three vaccination behaviours across 10 countries in Europe and Central Asia. Qualitative data from interviews and focus group discussions with 378 HCWs between December 2020 and March 2022 were synthesised and organised by four COM (capability, physical and social opportunity, motivation) factors. Differences by stage of COVID-19 vaccine roll-out (in preparation, early and late delivery) were explored. Receiving vaccination related to all four factors. Recommending vaccination mostly related to capability and motivation. HCWs were generally well-informed by official sources and viewed vaccination as the way to end the pandemic, acknowledging their important role in this. Colleagues, family and friends were positive influences on personal vaccination decisions. However, knowledge gaps were evident, particularly amongst nurses who relied on (social) media. Concerns about safety and effectiveness, often connected to knowledge gaps, were heightened by the accelerated timeline for COVID-19 vaccine development and approval. This impeded some HCWs’ motivation to receive and recommend vaccination even in the later roll-out countries. Delivering vaccination was facilitated by support from public health organisations, teamwork and service re-organisation, more evident amongst later roll-out countries. Ongoing high workloads, stress and burnout hindered delivery. Complex and inter-related factors affecting HCWs’ vaccination behaviours were identified. These insights should inform the design of multifaceted interventions (e.g., communication skills training, management support for HCWs’ mental health, and engaging them in decision-making for service redesign); not only for COVID-19 vaccination as it is integrated into routine services but for routine immunization as a whole.

Recordings of neural activity with further data interpretation and analysis are helping to discover underlying processes of the brain's functioning. These studies can have a huge impact on the development of modern highly promising technologies such are: cognitive computing, machine learning and artificial intelligence, human-machine interfaces, bionic prosthetic devices and etc. This has remarkably increased the interest in electrophysiological recordings. Although the technology and techniques of these recordings are being continuously improved, there are still many obstacles in getting high quality recorded data due to its complicated nature, small signal amplitudes and inherited noises. Every node in the recording system is crucial for getting meaningful and precision data. In this paper, a method for manufacturing of low-cost electrode arrays for electrophysiological recordings is described. The proposed electrode arrays are easy-to-replicate and can be easily modified, which gives flexibility for customized probe preparation. The testing shows that these probes have low electrical impedances and can be used for neural spike registration.

Major risk factors of head and neck squamous cell carcinoma (HNSCC) are tobacco use and human papillomavirus (HPV). HPV E6 oncoprotein leads to the degradation of the p53 protein, whereas HPV-negative cancers are frequently associated with TP53 mutations. Peposertib is a potent and selective, orally administered small-molecule inhibitor of the catalytic subunit of the DNA-dependent kinase (DNA-PKcs), a key regulator of non-homologous end joining (NHEJ). NHEJ inhibition along with irradiation (IR)-induced DNA double-strand breaks has the potential to increase antitumor treatment efficacy. Here, we investigated the responses of HNSCC models with distinct HPV and p53 status to treatments with IR, DNA-PKcs inhibition, and their combination. We observed that IR-induced DNA damage combined with peposertib administration shortly before IR results in decreased cell viability and proliferation and causes DNA repair delay in all the studied HNSCC cell lines. However, our data confirm that the actual cell fate upon this treatment is strongly dependent on cellular p53/HPV status. Cells lacking functional p53 due to its degradation by HPV or due to the presence of a loss-of-function mutation are arrested in the G2 phase of the cell cycle and eliminated by apoptosis whereas p53-proficient HNSCC cell lines undergo senescence. Consequently, HPV+ cancer cell lines and xenografts display stronger and more durable responses and seem to benefit from the combined treatment more than p53-proficient HNSCCs. In conclusion, DNA-PKcs inhibitor peposertib should be further studied as a potential radiosensitizer for HNSCCs, taking into consideration the genetic background and the HPV status of a particular tumor.

Long noncoding RNAs (lncRNAs) can act as tumour suppressors or oncogenes to repress/promote tumour cell proliferation via RNA-dependent mechanisms. Recently, genome sequencing has identified elevated densities of tumour somatic single nucleotide variants (SNVs) in lncRNA genes. However, this has been attributed to phenotypically-neutral passenger processes, and the existence of positively-selected fitness-altering driver SNVs acting via lncRNAs has not been addressed. We developed and used ExInAtor2, an improved driver-discovery pipeline, to map pancancer and cancer-specific mutated lncRNAs across an extensive cohort of 2583 primary and 3527 metastatic tumours. The 54 resulting lncRNAs are mostly linked to cancer for the first time. Their significance is supported by a range of clinical and genomic evidence, and display oncogenic potential when experimentally expressed in matched tumour models. Our results revealed a striking SNV hotspot in the iconic NEAT1 oncogene, which was ascribed by previous studies to passenger processes. To directly evaluate the functional significance of NEAT1 SNVs, we used in cellulo mutagenesis to introduce tumour-like mutations in the gene and observed a consequent increase in cell proliferation in both transformed and normal backgrounds. Mechanistic analyses revealed that SNVs alter NEAT1 ribonucleoprotein assembly and boost subnuclear paraspeckles. This is the first experimental evidence that mutated lncRNAs can contribute to the pathological fitness of tumour cells. Competing Interest Statement The authors have declared no competing interest. Footnotes * Correction to figure captions; Correction of misspelled words

Previous studies in Armenia have found low healthcare quality and satisfaction, with significant barriers to healthcare access and high out-of-pocket spending, especially in rural areas. This study is the first to utilize focus groups to better understand patient perceptions of healthcare quality in rural Armenia. Study participants were volunteers, mostly women and teachers, among 15 rural Armenian villages. Using the Lévesque model, we assessed participant responses using the domains of approachability, acceptability, availability and accommodation, affordability, and appropriateness. Our study found that many residents have low trust in physicians and the healthcare system, and associate higher quality of care with increased diagnostic testing and sub-specialty care. The interpersonal component of healthcare was an important factor in determining quality of care; residents voiced that high quality is characterized by providers who communicate clearly, have a compassionate demeanor, value patient preferences, and support patient autonomy. Residents also expressed positivity towards low cost of care. When discussing the quality of providers, residents noted that providers should communicate test results, and generally keep patients informed throughout the treatment process. In discussing barriers to access, residents noted poor roads and inconsistent physician availability. Our findings align with observations from studies in other LMIC settings on the topic of perceptions of healthcare quality while providing a more comprehensive understanding of previously reported low patient satisfaction rates and low quality of care in Armenia. We have provided targeted recommendations to improve rural healthcare in Armenia that include implementation of patient-centered care, required trainings for physicians and nurses, system-level strategies for improved utilization and outcomes, and co-produced health campaigns. Keywords: Healthcare perceptions, Healthcare quality, Armenia, Rural health, Community health, LMICs, Barriers to care, Focus group, Lévesque model

Previous studies in Armenia have found low healthcare quality and satisfaction, with significant barriers to healthcare access and high out-of-pocket spending, especially in rural areas. This study is the first to utilize focus groups to better understand patient perceptions of healthcare quality in rural Armenia. Study participants were volunteers, mostly women and teachers, among 15 rural Armenian villages. Using the Lévesque model, we assessed participant responses using the domains of approachability, acceptability, availability and accommodation, affordability, and appropriateness. Our study found that many residents have low trust in physicians and the healthcare system, and associate higher quality of care with increased diagnostic testing and sub-specialty care. The interpersonal component of healthcare was an important factor in determining quality of care; residents voiced that high quality is characterized by providers who communicate clearly, have a compassionate demeanor, value patient preferences, and support patient autonomy. Residents also expressed positivity towards low cost of care. When discussing the quality of providers, residents noted that providers should communicate test results, and generally keep patients informed throughout the treatment process. In discussing barriers to access, residents noted poor roads and inconsistent physician availability. Our findings align with observations from studies in other LMIC settings on the topic of perceptions of healthcare quality while providing a more comprehensive understanding of previously reported low patient satisfaction rates and low quality of care in Armenia. We have provided targeted recommendations to improve rural healthcare in Armenia that include implementation of patient-centered care, required trainings for physicians and nurses, system-level strategies for improved utilization and outcomes, and co-produced health campaigns.

[...]long-term follow-up studies have shown that patients who have experienced previous treatment failure contribute importantly to ongoing transmission in the community (2). The study was approved by the relevant health authorities in Armenia and met the exemption criteria set by the MSF ethics review board for a posteriori analyses of routinely collected clinical data. The inverseprobability-weighted regression adjustment analysis showed that patients in the CU cohort had an estimated statistically significant increase in treatment success of 30.2% (95% confidence interval, 15.8-44.5%). [...]new and repurposed drugs can make fluoroquinoloneresistant MDR-TB, and potentially XDR-TB, a disease that is curable in the majority of cases.