Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.

Background: Coronavirus disease 2019 (COVID-19) has become a global pandemic, affecting millions of people. However, the relationship between COVID-19 and acute cerebrovascular diseases (CVD) is unclear. Aims: We aimed to characterize the incidence, risk factors, clinical-radiological manifestations and outcome of COVID-19-associated stroke. Methods: Three medical databases were systematically reviewed for published articles on acute CVD in COVID-19 (December 2019-September 2020). The review protocol was previously registered (PROSPERO ID=CRD42020185476). Data were extracted from articles reporting 5 stroke cases in COVID-19. We complied with the PRISMA guidelines, and used the Newcastle–Ottawa Scale to assess data quality. Data were pooled using a random-effects model. Summary of review: Of 2,277 initially identified articles, 61 (2.7%) were entered in the meta-analysis. Out of 108,571 patients with COVID-19, acute CVD occurred in 1.4% (95%CI: 1.0-1.9). The most common manifestation was acute ischemic stroke (87.4%); intracerebral haemorrhage was less common (11.6%). Patients with COVID-19 developing acute CVD, compared to those who did not, were older (pooled median difference=4.8 years; 95%CI:1.7-22.4), more likely to have hypertension (OR=7.35; 95%CI:1.94-27.87), diabetes mellitus (OR=5.56; 95%CI:3.34-9.24), coronary artery disease (OR=3.12; 95%CI:1.61-6.02), and severe infection (OR=5.10; 95%CI:2.72-9.54). Compared to individuals who experienced a stroke without the infection, patients with COVID-19 and stroke were younger (pooled median difference=-6.0 years; 95%CI:-12.3 to -1.4), had higher NIHSS (pooled median difference=5; 95%CI:3-9), higher frequency of large vessel occlusion (OR=2.73; 95%CI:1.63-4.57), and higher in-hospital mortality rate (OR=5.21; 95% CI:3.43-7.90). Conclusions: Acute CVD is not uncommon in COVID-19, especially in those whom are severely infected and have pre-existing vascular risk factors. The pattern of large vessel occlusion and multi-territory infarcts suggest that cerebral thrombosis and/or thromboembolism could be possible causative pathways for the disease.

Highlights d Frequent overgrowth of lung cancer organoids by normal airway organoids d Copy number profiling and IHC can be used to distinguish tumor and normal organoids d Low establishment rate of pure lung cancer organoids limits their clinical utility

INTRODUCTION Woman-centered care has become a midwifery concept with implied meaning. In this paper we aim to provide a clear conceptual foundation of woman-centered care for midwifery science and practice. METHODS An advanced concept analysis was undertaken. At the outset, a systematic search of the literature was conducted in PubMed, OVID and EBSCO. This was followed by an assessment of maturity of the retrieved data. Principle-based evaluation was done to reveal epistemological, pragmatic, linguistic and logic principles, that attribute to the concept. Summative conclusions of each respective component and a detailed analysis of conceptual components (antecedents, attributes, outcomes, boundaries) resulted in a definition of woman-centered care. RESULTS Eight studies were selected for analyses. In midwifery, woman-centered care has both a philosophical and a pragmatic meaning. There is strong emphasis on the woman-midwife relationship during the childbearing period. The concept demonstrates a dual and equal focus on physical parameters of pregnancy and birth, and on humanistic dimensions in an interpersonal context. The concept is epistemological, dynamic and multidimensional. The results reveal the concept's boundaries and fluctuations regarding equity and control. The role of the unborn child is not incorporated in the concept. CONCLUSION An in-depth understanding and a broad conceptual foundation of womancentered care has evolved. Now, the concept is ready for research and educational purposes as well as for practical utility.

Non-small cell lung cancer (NSCLC) is the second most prevalent type of cancer. With the current treatment regimens, the mortality rate remains high. Therefore, better therapeutic approaches are necessary. NSCLCs generally possess many genetic mutations and are well infiltrated by T cells (TIL), making TIL therapy an attractive option. Here we show that T cells from treatment naive, stage I-IVa NSCLC tumors can effectively be isolated and expanded, with similar efficiency as from normal lung tissue. Importantly, 76% (13/17) of tested TIL products isolated from NSCLC lesions exhibited clear reactivity against primary tumor digests, with 0.5%-30% of T cells producing the inflammatory cytokine Interferon (IFN)-γ. Both CD4+ and CD8+ T cells displayed tumor reactivity. The cytokine production correlated well with CD137 and CD40L expression. Furthermore, almost half (7/17) of the TIL products contained polyfunctional T cells that produced Tumor Necrosis Factor (TNF)-α and/or IL-2 in addition to IFN-γ, a hallmark of effective immune responses. Tumor-reactivity in the TIL products correlated with high percentages of CD103+CD69+CD8+ T cell infiltrates in the tumor lesions, with PD-1hiCD4+ T cells, and with FoxP3+CD25+CD4+ regulatory T cell infiltrates, suggesting that the composition of T cell infiltrates may predict the level of tumor reactivity. In conclusion, the effective generation of tumor-reactive and polyfunctional TIL products implies that TIL therapy will be a successful treatment regimen for NSCLC patients.

To investigate the role of nitric oxide (NO) in bacterial meningitis, concentrations in serum, cerebrospinal fluid (CSF), or both of the precursor (L-arginine) and degradation products of NO (nitrate, nitrite) and tumor necrosis factor (TNF)-alpha were measured in 35 patients and 30 controls. CSF nitrate levels were significantly elevated, mainly due to increased blood-brain barrier permeability, and are therefore not a good parameter for gauging endogenous NO production in the CSF compartment. CSF NO/nitrite levels were significantly elevated in patients. NO/nitrite levels decreased over time (26%/6 h; P < .001). CSF levels of NO/nitrite correlated with those of TNF-alpha (r = .55; P = .001) and glucose (r = -.43; P = .02). CSF levels of L-arginine were lower in patients than in controls (P < .001). Dexamethasone did not exert a significant effect on NO metabolism. In conclusion, enhanced NO production may contribute to anaerobic glycolysis and neurologic damage in bacterial meningitis.

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