Notes

By using the data coming from studies without having events throughout meta-analyses associated with unfavorable events: the scientific exploration.
scent girls become empowered to exercise greater control over contraceptive use.Systematic testing of existing drugs and their combinations is an attractive strategy to exploit approved drugs for repurposing and identify the best actionable treatment options. To expedite the search among many possible drug combinations, we designed a combinatorial CRISPR-Cas9 screen to inhibit druggable targets. Co-blockade of the N-methyl-D-aspartate receptor (NMDAR) with targets of first-line kinase inhibitors reduced hepatocellular carcinoma (HCC) cell growth. Clinically, HCC patients with low NMDAR1 expression showed better survival. The clinically approved NMDAR antagonist ifenprodil synergized with sorafenib to induce the unfolded protein response, trigger cell cycle arrest, downregulate genes associated with WNT signaling and stemness, and reduce self-renewal ability of HCC cells. In multiple HCC patient-derived organoids and human tumor xenograft models, the drug combination, but neither single drug alone, markedly reduced tumor-initiating cancer cell frequency. Since ifenprodil has an established safety history for its use as a vasodilator in humans, our findings support the repurposing of this drug as an adjunct for HCC treatment to improve clinical outcome and reduce tumor recurrence. These results also validate an approach for readily discovering actionable combinations for cancer therapy.Metastasis is the main cause of cancer-related mortality. see more Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechano-structural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse mode harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immuno-deprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer.Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiological significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 lung cancer patients in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compound had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, PD-L1 expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared to tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy.Neoadjuvant immunotherapy, given before surgical resection, is a promising approach to develop systemic antitumor immunity for the treatment of high-risk resectable disease. Here, using syngeneic and orthotopic mouse models of triple-negative breast cancer, we have tested the hypothesis that generation of tumor-specific T-cell responses by induction and activation of tumor-residing Batf3-dependent conventional type 1 dendritic cells (cDC1) before resection improves control of distant metastatic disease and survival. Mice bearing highly metastatic orthotopic tumors were treated with a combinatorial in situ immunomodulation (ISIM) regimen comprised of intratumoral administration of Flt3L, local radiotherapy, and in situ TLR3/CD40 stimulations, followed by surgical resection. Neoadjuvant ISIM generated tumor-specific CD8+ T cells that infiltrated into distant non-irradiated metastatic sites, which delayed the progression of lung metastases and improved survival after the resection of primary tumors. The efficacy of neoadjuvant ISIM was dependent on de novo adaptive T-cell immunity elicited by Batf3-dependent DCs and was enhanced by increasing dose and fractionation of radiotherapy, and early surgical resection after the completion of neoadjuvant ISIM. Importantly, neoadjuvant ISIM synergized with PD-L1 blockade to improve control of distant metastases and prolong survival, while removal of tumor-draining lymph nodes abrogated the antimetastatic efficacy of neoadjuvant ISIM. Our findings illustrate the therapeutic potential of neoadjuvant multimodal intralesional therapy for the treatment of resectable tumors with high risk of relapse.
To propose diagnostic criteria for a presumed incipient choroidal melanoma based on tumour growth rate and tumour doubling time (TDT) and to describe management of such tumours with transpupillary thermotherapy (TTT).

Retrospective interventional case series of nine consecutive presumed incipient uveal melanomas diagnosed and treated with TTT in 2010-2017. Growth rate in mm/year and per cent/year in largest basal diameter (LBD) and TDT were compared with published data for uveal melanomas and growing naevi that did not transform to melanoma under long-term follow-up.

The median LBD and thickness were 1.6 mm (range 0.9-2.3) and 0.20 mm (range 0.15-0.29), respectively. The median age was 57 years (range 47-78). Seven tumours were classified as de novo melanomas and two as transformed naevi. The median time from first observation to diagnosis was 3.3 years (range 2.2-7.3), LBD growth rate 0.25 mm/year (range 0.11-0.72) and 34 per cent/year (range 10-1437), and TDT 609 days (range 97-1612). The estimates matched those reported for uveal melanoma (median TDT 521 days, 90th percentile 2192) and exceeded those for growing naevi (median growth rate 0.04 mm/year, 90th percentile 0.12; 1.1 per cent/year, 90th percentile 2.6). The predicted median age at de novo appearance was 51 years (range 32-63). No tumour grew after TTT during a median follow-up of 2.1 years (range 0.6-8.7).

In this series, relative growth rate and TDT best qualified as diagnostic criteria for an incipient choroidal melanoma. Too small for brachytherapy, they could be managed with TTT.
In this series, relative growth rate and TDT best qualified as diagnostic criteria for an incipient choroidal melanoma. Too small for brachytherapy, they could be managed with TTT.A tumor-penetrating bicyclic peptide that delivers a toxic payload may have finally unlocked the therapeutic potential of targeting EphA2. According to phase I trial data, BT5528 yielded clinical responses in three patients with ovarian and urothelial cancers-without any of the toxicity issues that have plagued other EphA2-directed therapeutic candidates.
Vaccine nationalism has become a key topic of discussion during the development, testing, and rollout of COVID-19 vaccines. Media attention has highlighted the ways that global, coordinated access to vaccines has been limited during the pandemic. It has also exposed how some countries have secured vaccine supply, through bilateral purchase agreements and the way pharmaceutical companies have priced, negotiated, and delivered these supplies. Much of the focus of this debate has been on the vaccine supply 'winners' and 'losers', but the voices of public opinion have been more limited.

We explore the concepts of vaccine nationalism and internationalism from the perspective of vaccine trial participants, using an empirical perspectives study that involved interviews with phase I/II COVID-19 vaccine trial participants in Oxford, UK. We surveyed and interviewed participants between September and October 2020 about their views, motivations and experiences in taking part in the trial.

First, we show how trial pionalism is strongly attached to national character and, therefore, it is more difficult for ownership of a vaccine to be though of as international.
Global surgery has recently gained prominence as an academic discipline within global health. Authorship inequity has been a consistent feature of global health publications, with over-representation of authors from high-income countries (HICs), and disenfranchisement of researchers from low-income and middle-income countries (LMICs). In this study, we investigated authorship demographics within recently published global surgery literature.

We performed a systematic analysis of author characteristics, including gender, seniority and institutional affiliation, for global surgery studies published between 2016 and 2020 and indexed in the PubMed database. We compared the distribution of author gender and seniority across studies related to different topics; between authors affiliated with HICs and LMICs; and across studies with different authorship networks.

1240 articles were included for analysis. Most authors were male (60%), affiliated only with HICs (51%) and of high seniority (55% were fully qualified specialist or generalist clinicians, Principal Investigators, or in senior leadership or management roles). The proportion of male authors increased with increasing seniority for last and middle authors. Studies related to Obstetrics and Gynaecology had similar numbers of male and female authors, whereas there were more male authors in studies related to surgery (69% male) and Anaesthesia and Critical care (65% male). Compared with HIC authors, LMIC authors had a lower proportion of female authors at every seniority grade. This gender gap among LMIC middle authors was reduced in studies where all authors were affiliated only with LMICs.

Authorship disparities are evident within global surgery academia. Remedial actions to address the lack of authorship opportunities for LMIC authors and female authors are required.
Authorship disparities are evident within global surgery academia. Remedial actions to address the lack of authorship opportunities for LMIC authors and female authors are required.
Income is a key social determinant of health yet it is rare for data on income to be routinely collected and integrated with electronic health records.

To examine response bias and evaluate patient perspectives of being asked about income in primary care.

Mixed-methods study in a large, multi-site primary care organization in Toronto, Canada where patients are asked about income in a routinely administered sociodemographic survey.

We examined data from the electronic health records of patients who answered at least one question on the survey between December 2013 and March 2016 (n=14,247). We compared those who responded to the income question to non-responders. We also conducted structured interviews with 27 patients.

10,441 (73%) patients responded to both parts of the income question. Female patients, minorities, caregivers of young children and seniors were less likely to respond. From interviews, many patients were comfortable answering the income question, particularly if they understood the connection between income and health, and believed the data would be used to improve care.
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