IMPORTANCE Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.OBJECTIVE To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS FRESCO (Fruquintinib Efficacy and Safety in 3+ LineColorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017.INTERVENTIONS Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURESThe primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded Ն8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTSOf the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% ( 27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.CONCLUSIONS AND RELEVANCE Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China.

BackgroundThe pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated α-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of α-synuclein is relevant to the pathogenesis of PD is unknown.Methodology/Principal FindingsIn this study, effect of nitrated α-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-α-synuclein intracellular. We provide evidence to show that the nitrated α-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated α-synuclein. Moreover, we show that administration of nitrated α-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D2R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated α-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified α-synuclein had significantly less severe behavioral effects.Conclusions/SignificanceOur results provide evidence that α-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.

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LINGO-1 is a component of the tripartite receptor complexes, which act as a convergent mediator of the intracellular signaling in response to myelin-associated inhibitors and lead to collapse of growth cone and inhibition of neurite extension. Although the function of LINGO-1 has been intensively studied, its downstream signaling remains elusive. In the present study, a novel interaction between LINGO-1 and a serine-threonine kinase WNK1 was identified by yeast two-hybrid screen. The interaction was further validated by fluorescence resonance energy transfer and co-immunoprecipitation, and this interaction was intensified by Nogo66 treatment. Morphological evidences showed that WNK1 and LINGO-1 were co-localized in cortical neurons. Furthermore, either suppressing WNK1 expression by RNA interference or overexpression of WNK1-(123-510) attenuated Nogo66-induced inhibition of neurite extension and inhibited the activation of RhoA. Moreover, WNK1 was identified to interact with Rho-GDI1, and this interaction was attenuated by Nogo66 treatment, further indicating its regulatory effect on RhoA activation. Taken together, our results suggest that WNK1 is a novel signaling molecule involved in regulation of LINGO-1 mediated inhibition of neurite extension.

Recurrent mutations of isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) have recently been studied in adult patients with acute myeloid leukemia (AML). A meta-analysis was performed to demonstrate their controversial prognostic impacts. The associations of IDH1 or IDH2 mutations with other molecular abnormalities were also investigated. In patients with AML, IDH1/2 mutations were significantly associated with normal karyotype and isolated trisomy 8 (p < .05). After adjusting for well-studied prognostic factors, IDH1 mutation seems to be associated with subtle but significantly inferior event-free survival (EFS) (p = 0.02) and possible adverse overall survival (OS) (p = 0.13) in patients with AML, especially in the favorable genotype subset with mutated NPM1 but without FLT3-ITD mutation (p < 0.05). Longer OS (p = 0.01) and better EFS tendency (p = 0.18) are implicated in patients with IDH2 mutations, which suggests that IDH2 mutations appear to confer a favorable prognosis. Moreover, IDH1 and IDH2 mutations may play a more important role in abnormal cytogenetics subgroups such as isolated trisomy 8. Screening of IDH1/2 mutations could help to identify patients at high risk within some subsets of AML.

Background. Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for refractory mCRC patients.

The loss of skeletal muscle mass and function is defined as sarcopenia, which might develop in elderly patients with cancers. It has been indicated as a potential negative factor in the survival of patients with malignant tumours. The aim of this systematic review and meta-analysis was to evaluate the associations between sarcopenia and survival outcomes or postoperative complications in patients with oesophageal cancer (EC). Web of Science, Embase, Medline, and Cochrane Library databases were searched until 10 May 2022, using keywords: sarcopenia, oesophageal cancer, and prognosis. Studies investigating the prognostic value of sarcopenia on EC survival were included. Forest plots and summary effect models were used to show the result of this meta-analysis. The quality of included studies was evaluated with the Newcastle-Ottawa Scale (NOS). A total of 1436 studies were identified from the initial search of four databases, and 41 studies were included for the final quantitative analysis. This meta-analysis revealed a significant association between sarcopenia and overall survival (OS) [hazard ratios (HR):1.68, 95% confidence interval (CI):1.54-1.83, P = 0.004, I 2 = 41.7%] or disease-free survival (DFS) 1.97 (HR: 1.97, 95% CI: 1.44-2.69, P = 0.007, I 2 = 61.9%) of EC patients. Subgroup analysis showed that sarcopenia remained a consistent negative predictor of survival when stratified by different treatment methods, populations, or sarcopenia measurements. Sarcopenia was also a risk factor for postoperative complications with a pooled odds ratio of 1.47 (95% CI: 1.21-1.77, P = 0.094, I 2 = 32.7%). The NOS scores of all included studies were ≥6, and the quality of the evidence was relatively high. The results from the study suggested that sarcopenia was significantly associated with both survival outcomes and postoperative complications in EC patients. Sarcopenia should be appropriately diagnosed and treated for improving short-term and long-term outcomes of patients with EC.

Early biomarkers of therapeutic responses can help optimize the treatment of metastatic colorectal cancers (mCRC). In this prospective exploratory study, we examined serial changes of plasma-circulating tumor DNA (ctDNA) in 41 mCRC patients receiving first-line chemotherapies and tested its association with treatment outcomes according to radiological assessments. Using next-generation sequencing technologies, we profiled somatic mutations in 50 cancer-related genes in ctDNA before each of the first four treatment cycles. We observed mutations in 95.7% of pre-treatment ctDNA samples. Using mutations of the maximal frequency in each pre-treatment plasma ctDNA sample as the candidate targets, we computed log2 fold changes of ctDNA levels between adjacent treatment cycles. We found that ctDNA reductions as early as prior to cycle 2 predicted responses after cycle 4. Log2 fold changes of ctDNA after cycle 1 (ctDNA log2 (C1/C0)) > −0.126 predicted progressive disease, with an accuracy of 94.6%. These patients also showed significantly worse progression-free survival than those with ctDNA log2 (C1/C0) ≤ −0.126 (median 2.0 vs. 9.0 months; P = 0.007). Together, the present exploratory study suggests that early changes in ctDNA levels detected via targeted sequencing are potential biomarkers of future treatment responses in mCRCs.