T cells play a key role in cell-mediated immunity, and strategies to genetically modify T cells, including chimeric antigen receptor (CAR) T cell therapy and T cell receptor (TCR) T cell therapy, ...have achieved substantial advances in the treatment of malignant tumors. In clinical trials, CAR-T cell and TCR-T cell therapies have produced encouraging clinical outcomes, thereby demonstrating their therapeutic potential in mitigating tumor development. This article summarizes the current applications of CAR-T cell and TCR-T cell therapies in clinical trials worldwide. It is predicted that genetically engineered T cell immunotherapies will become safe, well-tolerated, and effective therapeutics and bring hope to cancer patients.
Background
At present, the severity of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been a focal point.
Methods
To assess the factors associated with ...severity and prognosis of patients infected with SARS‐CoV‐2, we retrospectively investigated the clinical, imaging and laboratory characteristics of confirmed 280 cases of novel coronavirus disease (COVID‐19) from 20 January to 20 February 2020.
Results
The median age of patients in the mild group was 37.55 years, whilst that in the severe group was 63.04 years. The proportion of patients aged over 65 years in the severe group was significantly higher than that of the mild group (59.04% vs. 10.15%, P < 0.05). 85.54% of severe patients had diabetes or cardiovascular diseases, which was significantly higher than that of the mild group (51.81% vs. 7.11%, P = 0.025; 33.73% vs. 3.05%, P = 0.042). Patients in the mild group experienced earlier initiation of antiviral treatment (1.19 ± 0.45 vs. 2.65 ± 1.06 days in the severe group, P < 0.001). Our study showed that comorbidity, time from illness onset to antiviral treatment and age >=65 were three major risk factors for COVID‐19 progression, whilst comorbidity and time from illness onset to antiviral treatment were two major risk factors for COVID‐19 recovery.
Conclusions
The elderly and patients with underlying diseases are more likely to experience a severe progression of COVID‐19. It is recommended that timely antiviral treatment should be initiated to slow the disease progression and improve the prognosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a critical mediator of p53-dependent and -independent apoptosis induced by a wide variety of ...stimuli, including genotoxic stress, deregulated oncogene expression, toxins, altered redox status, growth factor/cytokine withdrawal and infection. It serves as a proximal signaling molecule whose expression is regulated by transcription factors in response to these stimuli. PUMA transduces death signals primarily to the mitochondria, where it acts indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members. It directly binds and antagonizes all known antiapoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. PUMA ablation or inhibition leads to apoptosis deficiency underlying increased risks for cancer development and therapeutic resistance. Although elevated PUMA expression elicits profound chemo- and radiosensitization in cancer cells, inhibition of PUMA expression may be useful for curbing excessive cell death associated with tissue injury and degenerative diseases. Therefore, PUMA is a general sensor of cell death stimuli and a promising drug target for cancer therapy and tissue damage.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Postoperative complications have a great impact on the postoperative course and oncological outcomes following major cancer surgery. Among them, infective complications play an important ...role. The aim of this study was to evaluate whether postoperative infective complications influence long‐term survival after liver resection for hepatocellular carcinoma (HCC).
Methods
Patients who underwent resection with curative intent for HCC between July 2003 and June 2016 were identified from a multicentre database (8 institutions) and analysed retrospectively. Independent risk factors for postoperative infective complications were identified. After excluding patients who died 90 days or less after surgery, overall survival (OS) and recurrence‐free survival (RFS) were compared between patients with and without postoperative infective complications within 30 days after resection.
Results
Among 2442 patients identified, 332 (13·6 per cent) had postoperative infective complications. Age over 60 years, diabetes mellitus, obesity, cirrhosis, intraoperative blood transfusion, duration of surgery exceeding 180 min and major hepatectomy were identified as independent risk factors for postoperative infective complications. Univariable analysis revealed that median OS and RFS were poorer among patients with postoperative infective complications than among patients without (54·3 versus 86·8 months, and 22·6 versus 43·2 months, respectively; both P < 0·001). After adjustment for other prognostic factors, multivariable Cox regression analyses identified postoperative infective complications as independently associated with decreased OS (hazard ratio (HR) 1·20, 95 per cent c.i. 1·02 to 1·41; P = 0·027) and RFS (HR 1·19, 1·03 to 1·37; P = 0·021).
Conclusion
Postoperative infective complications decreased long‐term OS and RFS in patients treated with liver resection for HCC.
From a multi‐institutional database, 2442 patients who underwent resection with curative intent for hepatocellular carcinoma between 2003 and 2016 were analysed retrospectively. Among them, 332 patients (13·6 per cent) had postoperative infective complications within 30 days after surgery. Multivariable Cox regression revealed that postoperative infective complications decreased long‐term overall and recurrence‐free survival after liver resection for hepatocellular carcinoma.
Complications decrease long‐term overall survival
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Adoptive cell therapy (ACT) is a kind of immunotherapy in which T cells are genetically modified to express a chimeric antigen receptor (CAR) or T cell receptor (TCR), and ACT has made a great ...difference in treating multiple types of tumors. ACT is not perfect, and it can be followed by severe side effects, which hampers the application of ACT in clinical trials. One of the most promising methods to minimize side effects is to endow adoptive T cells with the ability to target neoantigens, which are specific to tumor cells. With the development of antigen screening technologies, more methods can be applied to discover neoantigens in cancer cells, such as whole-exome sequencing combined with mass spectrometry, neoantigen screening through an inventory-shared neoantigen peptide library, and neoantigen discovery via trogocytosis. In this review, we focus on the side effects of existing antigens and their solutions, illustrate the strategies of finding neoantigens in CAR-T and TCR-T therapies through methods reported by other researchers, and summarize the clinical behavior of these neoantigens.
Polyelectrolyte brushes provide wear protection and lubrication in many technical, medical, physiological, and biological applications. Wear resistance and low friction are attributed to counterion ...osmotic pressure and the hydration layer surrounding the charged polymer segments. However, the presence of multivalent counterions in solution can strongly affect the interchain interactions and structural properties of brush layers. We evaluated the lubrication properties of polystyrene sulfonate brush layers sliding against each other in aqueous solutions containing increasing concentrations of counterions. The presence of multivalent ions (Y
, Ca
, Ba
), even at minute concentrations, markedly increases the friction forces between brush layers owing to electrostatic bridging and brush collapse. Our results suggest that the lubricating properties of polyelectrolyte brushes in multivalent solution are hindered relative to those in monovalent solution.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
The early part of the last deglaciation is characterised by a ~40 ppm atmospheric CO2 rise occurring in two abrupt phases. The underlying mechanisms driving these increases remain a subject of ...intense debate. Here, we successfully reproduce changes in CO2, δ13C and Δ14C as recorded by paleo-records during Heinrich stadial 1 (HS1). We show that HS1 CO2 increase can be explained by enhanced Southern Ocean upwelling of carbon-rich Pacific deep and intermediate waters, resulting from intensified Southern Ocean convection and Southern Hemisphere (SH) westerlies. While enhanced Antarctic Bottom Water formation leads to a millennial CO2 outgassing, intensified SH westerlies induce a multi-decadal atmospheric CO2 rise. A strengthening of SH westerlies in a global eddy-permitting ocean model further supports a multi-decadal CO2 outgassing from the Southern Ocean. Our results highlight the crucial role of SH westerlies in the global climate and carbon cycle system with important implications for future climate projections.
Colorectal cancer (CRC), the second leading cause of cancer-related deaths in the US, has been treated with targeted therapies. However, the mechanisms of differential responses and resistance of ...CRCs to targeted therapies are not well understood. In this study, we found that genetic alterations of FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7-inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA or p53. These cells are defective in apoptosis owing to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug-resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance. Together, our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies, and Mcl-1 as an attractive therapeutic target.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone ...modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment. In this review, we summarized the recent discoveries linking epigenetics and metabolism and their underlying roles in tumorigenesis; and highlighted the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these abnormalities in cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Neuroendocrine prostate cancer (NEPC) has increasingly become a clinical challenge. The mechanisms by which neuroendocrine (NE) cells arises from prostate adenocarcinoma cells are poorly understood. ...FOXA1 is a transcription factor of the forkhead family that is required for prostate epithelial differentiation. In this study, we demonstrated that FOXA1 loss drives NE differentiation, demarcated by phenotypical changes and NEPC marker expressions. Mechanistically, this is mediated by FOXA1 binding to the promoter of interleukin 8 (IL-8), a chemokine previously shown elevated in NEPC, to directly inhibit its expression. Further, IL-8 upregulation activates the MAPK/ERK pathway, leading to ERK phosphorylation and enolase 2 (ENO2) expression. IL-8 knockdown or ERK inhibition, on the other hand, abolished FOXA1 loss-induced NE differentiation. Analysis of xenograft mouse models confirmed FOXA1 loss in NEPC tumors relative to its adenocarcinoma counterparts. Importantly, FOXA1 is downregulated in human NEPC tumors compared to primary and castration-resistant prostate cancers, and its expression is negatively correlated with that of ENO2. These findings indicate that FOXA1 transcriptionally suppresses IL-8, the expression of which would otherwise stimulate the MAPK/ERK pathway to promote NE differentiation of prostate cancer cells. Our data strongly suggest that FOXA1 loss may play a significant role in enabling prostate cancer progression to NEPC, whereas IL-8 and MAPK/ERK pathways may be promising targets for therapeutic intervention.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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