Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.

101 women; median age was 47•5 years (range 7-90). The most common symptoms at onset of illness were fever (193 [84%] patients), cough (159 [69%] patients), and sputum production (98 [43%] patients). Diarrhoea was observed in 49 (21%) patients. Patients with diarrhoea were older and were more likely to have comorbidities than patients without diarrhoea (table). A greater proportion of patients admitted to hospital had diarrhoea as the outbreak progressed: nine (43%) of 21 patients admitted between Feb 12 and March 6, 2020, had diarrhoea versus 40 (19%) of 209 patients admitted between Jan 19 and Feb 11, 2020.More patients with diarrhoea showed severe symptoms of pneumonia hospitals in Guangdong province, two in Hubei province, and ten in Jiangxi province) between Jan 19, 2020, and March 6, 2020. Most patients were admitted because of fever, cough, dyspnoea, and chest CT findings consistent with COVID-19 pneumonia. Diagnosis of COVID-19 was based on positive SARS-CoV-2 RNA tests. Two patients with pre-existing digestive diseases were excluded from our analysis. The analysis was approved by the institutional review boards of Sun Yat-sen University and the participating hospitals. Full details of the methods used are in the appendix (p 1).The clinical and demographic characteristics of the 230 patients analysed are shown in the appendix (p 2). There were 129 men and

ObjectiveTo better understand the origins, manifestations and current policy responses to patient–physician mistrust in China.DesignQualitative study using in-depth interviews focused on personal experiences of patient–physician mistrust and trust.SettingGuangdong Province, China.ParticipantsOne hundred and sixty patients, patient family members, physicians, nurses and hospital administrators at seven hospitals varying in type, geography and stages of achieving goals of health reform. These interviews included purposive selection of individuals who had experienced both trustful and mistrustful patient–physician relationships.ResultsOne of the most prominent forces driving patient–physician mistrust was a patient perception of injustice within the medical sphere, related to profit mongering, knowledge imbalances and physician conflicts of interest. Individual physicians, departments and hospitals were explicitly incentivised to generate revenue without evaluation of caregiving. Physicians did not receive training in negotiating medical disputes or humanistic principles that underpin caregiving. Patient–physician mistrust precipitated medical disputes leading to the following outcomes: non-resolution with patient resentment towards physicians; violent resolution such as physical and verbal attacks against physicians; and non-violent resolution such as hospital-mediated dispute resolution. Policy responses to violence included increased hospital security forces, which inadvertently fuelled mistrust. Instead of encouraging communication that facilitated resolution, medical disputes sometimes ignited a vicious cycle leading to mob violence. However, patient–physician interactions at one hospital that has implemented a primary care model embodying health reform goals showed improved patient–physician trust.ConclusionsThe blind pursuit of financial profits at a systems level has eroded patient–physician trust in China. Restructuring incentives, reforming medical education and promoting caregiving are pathways towards restoring trust. Assessing and valuing the quality of caregiving is essential for transitioning away from entrenched profit-focused models. Moral, in addition to regulatory and legal, responses are urgently needed to restore trust.

Purpose: Although many biological processes are involved in the modification of N 6 -methyladenosine (m 6 A), the exact role of m 6 A in the development of malignant tumors remains unclear. Methyltransferase 3 (METTL3) is a major RNA N 6 -methyladenosine methyltransferase. We aimed to explore the role of METTL3 in colorectal cancer (CRC) carcinogenesis and disease progression. Methods: In this study, immunohistochemistry was performed with a tissue microarray. qRT-PCR and Western blots were used to evaluate the expression of METTL3 in CRC cells. The effect of METTL3 on cell proliferation, migration and invasion of CRC cells was examined by IncuCyte Live Cell Analysis System and transwell assay, respectively. Results: The results suggested that positive expression of METTL3 was significantly associated with longer survival time ( P =0.011). We next demonstrated that overexpression of METTL3 could inhibit proliferation, migration and invasion in CRC cells, while downregulation of METTL3 shows the opposite result. Furthermore, downregulation of METTL3 resulted in activation of p-p38 and p-ERK. Moreover, the inhibitors of p38 or ERK kinase could significantly reverse the effect of migration and invasion, which was induced by knockdown of METTL3. Conclusion: We concluded that METTL3 played a tumor-suppressive role in CRC cell proliferation, migration and invasion through p38/ERK pathways, which indicated that METTL3 might be a novel marker for CRC carcinogenesis, progression and survival.