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Elliptic curve cryptography is an important part of nowaday’s public key cryptosystem. Counting points of elliptic curves over finite fields is of great significance to the selection of safety curves. At present, there are many p-adic algorithms, such as SST algorithm, generalized AGM algorithm, Kedlaya algorithm, etc., which can deal with the situation of finite fields of small characteristics. In this paper, the authors generalize the MSST algorithm of characteristic 2 to general fields of odd characteristic, and propose the generalized MSST algorithm. The generalized MSST algorithm is achieved by combining the advantages of the SST algorithm and the generalized AGM algorithm. If the time complexity of the multiplication of two n-bit numbers is denoted as O(nμ), then the time complexity of the generalized MSST algorithm is O(n2μ+11+μ), which is the same as the improved SST algorithm. In practical experiments, the running time of the generalized MSST algorithm is less than that of the improved SST algorithm.

ABSTRACTBevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation.Abbreviations:2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.

BRAFand MLH1promoter methylation testings have been proven effective prescreens for Lynch Syndrome. We aimed to compare different screening strategies for Lynch Syndrome in patients with MLH1(−) CRC. Patients with MLH1(−) CRC who had been tested for BRAFmutation and germline variants of DNA mismatch repair genes were included. We compared the sensitivities and specificities for identifying Lynch Syndrome and the cost-effectiveness of four screening approaches that used the following tests as prescreens: BRAFtesting, MLH1methylation testing, MLH1methylation & BRAFtesting, and MLH1methylation testing & Revised Bethesda Criteria. Of 109 patients included, 23 (21.1%) were Lynch Syndrome patients. BRAFmutation and MLH1methylation occurred in 6 (5.5%) and 40 (36.7%) patients, respectively. The sensitivity for identifying Lynch syndrome of BRAFtesting was 100%, but the specificity was only 7%. MLH1methylation testing had a lower sensitivity than BRAFtesting (97.5% vs 100%), but had a markedly higher specificity (45.3% vs 7%). The combination of the two testings had a slightly higher specificity than MLH1methylation testing alone (47.7% vs 45.3%). The MLH1methylation testing approach had a 10% lower cost of identifying MLH1(−) Lynch syndrome carriers per case than universal genetic testing, but it missed 4.5% of patients. BRAFand MLH1promoter methylation testings as prescreens for Lynch syndrome are less effective in Chinese patients with MLH1(−) CRC than in their Western counterparts. Universal genetic testing could be considered an up-front option for this population.

ABSTRACTThis study aimed to validate the prognostic value of Immunoscore (IS) in stage II colorectal cancer (CRC), and explore the roles of IS and circulating tumor DNA (ctDNA) in the adjuvant treatment for early-stage CRC. Resected tumor samples from stage II CRC patients were collected from the Sun Yat-sen University Cancer Center. The densities of CD3+ and CD8+ lymphocytes were quantified and converted to IS and classified into Low, Intermediate (Int), and High groups according to predefined cutoffs. A total of 113 patients were included in the study. Patients with IS-High, Int, and Low were 43 (38%), 62 (55%), and 8 (7%), respectively. Patients with IS-High had an excellent clinical outcome, with none recurring during a median follow-up of 3 years, including 15 (35%) clinical high-risk patients. The 3-year disease-free survival (DFS) was 100% for IS-High, 76% for IS-Int, and 47% for IS-Low (P < .001). In the multivariate Cox analysis, IS was the only significant parameter associated with DFS. IS-Int and IS-Low patients with adjuvant chemotherapy had improved DFS compared to those who did not receive adjuvant chemotherapy (HR = 0.3; 95% CI 0.1–0.92; P = .026). Among the 49 patients with postoperative ctDNA data, IS-High patients had the lowest ctDNA positivity rate, suggesting that they were most eligible for chemotherapy-free treatment. IS had a strong prognostic value in Chinese patients with stage II CRC and demonstrates its clinical utility. IS and ctDNA will jointly optimize the adjuvant treatment strategies for early-stage CRC.

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3upregulation can subvert therapy-induced anticancer immunosurveillance. Stress reduces the effects of various cancer therapies, such as chemotherapy and immunotherapy, in mice; this is mediated, at least partially, through Tsc22d3 upregulation in tumor-infiltrating dendritic cells, which leads to immunosuppression.

•1.Escalating imatinib dosage or directly switch to sunitinib in GISTs failing on standard dose of imatinib is still controversial.•2.After the progression of imatinib standard-dose treatment in recurrent/metastatic GISTs, the progression-free survival (PFS) of patients directly switching to sunitinib was significantly longer compared with the PFS of patients with imatinib dose escalation in our study.•3.Sunitinib was a more effective TKI with an improved PFS for GISTs after the progression of standard dose of imatinib.•4.Under the circumstance that the overall survival (OS) in the two groups was similar, it was suggested that the curative effect of imatinib dose escalation followed by sunitinib was also considerable, and we could not deny its feasibility.

This study aimed to evaluate the safety and efficacy of a new nickel-titanium shape memory alloy compression anastomosis ring, NiTi CAR 27, in constructing an anastomosis for colorectal cancer resection compared with conventional staples.

Pathological complete response has shown a better prognosis for patients with locally advanced rectal cancer after preoperative chemoradiotherapy. However, correlations between post-chemoradiotherapy clinical factors and pathologic complete response are not well confirmed. The aim of the current study was to identify post-chemoradiotherapy clinical factors that could serve as indicators of pathologic complete response in locally advanced rectal cancer.

Chronic pain is thought to be partly caused by a loss of GABAergic inhibition and resultant neuronal hyperactivation in the central pain-modulating system, but the underlying mechanisms for pain-modulating neurons in the brain are unclear. In this study, we investigated the cellular mechanisms for activation of brainstem descending pain facilitation in rats under persistent pain conditions. In the nucleus raphe magnus (NRM), a critical relay in the brain’s descending pain-modulating system, persistent inflammatory pain induced by complete Freund’s adjuvant decreased the protein level of K+–Cl−cotransporter (KCC2) in both total and synaptosomal preparations. Persistent pain also shifted the equilibrium potential of GABAergic inhibitory postsynaptic current (EIPSC) to a more positive level and increased the firing of evoked action potentials selectively in μ-opioid receptor (MOR)–expressing NRM neurons, but not in MOR-lacking NRM neurons. Microinjection of brain-derived neurotrophic factor (BDNF) into the NRM inhibited the KCC2 protein level in the NRM, and both BDNF administration and KCC2 inhibition by furosemide mimicked the pain-induced effects on EIPSCand excitability in MOR-expressing neurons. Furthermore, inhibiting BDNF signaling by NRM infusion of tyrosine receptor kinase B–IgG or blocking KCC2 with furosemide prevented these pain effects in MOR-expressing neurons. These findings demonstrate a cellular mechanism by which the hyperactivity of NRM MOR-expressing neurons, presumably responsible for descending pain facilitation, contributes to pain sensitization through the signaling cascade of BDNF-KCC2-GABA impairment in the development of chronic pain.

Membrane trafficking of the δ-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as long-term opioid exposure, represents unique receptor plasticity involved in the mechanisms of long-term opioid effects in opioid addiction and opioid treatment of chronic pain. However, the signaling pathways coupled to the newly emerged functional DOR in central neurons are largely unknown at present. In this study, we investigated the signaling cascades of long-term morphine-induced DOR for its cellular and behavioral effects in neurons of the rat brainstem nucleus raphe magnus (NRM), a key supraspinal site for opioid analgesia. We found that, among the three phospholipase A2(PLA2)-regulated arachidonic acid (AA) metabolic pathways of lipoxygenase, cyclooxygenase, and epoxygenase, 12-lipoxygenase of the lipoxygenase pathway primarily mediated DOR inhibition of GABA synaptic transmission, because inhibitors of 12-lipoxygenase as well as lipoxygenases and PLA2largely blocked the DOR- or AA-induced GABA inhibition in NRM neurons in brainstem slices in vitro. Blockade of the epoxygenase pathway was ineffective, whereas blocking either 5-lipoxygenase of the lipoxygenase pathway or the cyclooxygenase pathway enhanced the DOR-mediated GABA inhibition. Behaviorally in rats in vivo, NRM infusion of 12-lipoxygenase inhibitors significantly reduced DOR-induced antinociceptive effect whereas inhibitors of 5-lipoxygenase and cyclooxygenase augmented the DOR antinociception. These findings suggest the PLA2-AA-12-lipoxygenase pathway as a primary signaling cascade for DOR-mediated analgesia through inhibition of GABA neurotransmission and indicate potential therapeutic benefits of combining 5-lipoxygenase and cyclooxygenase inhibitors for maximal pain inhibition.

Gad2encodes GAD65, which is present preferentially in presynaptic terminals for synthesis of GABA for vesicle release. Gad2is a regulatory target of cell activities in various brain functions and in GABA perturbation-related neurological diseases. However, our understanding of how Gad2is transcriptionally regulated and how Gad2transcription responds to changing cell environment under these conditions is still limited. This review discusses recent advances in the regulatory mechanisms for Gad2transcription and highlights the characteristics of TATA-less Gad2promoters and regulation of Gad2transcription by CREB and by activity-dependent epigenetic modification of the chromatin structure in regulatory elements of the Gad2gene.

Production of neurons from non‐neural cells has far‐reaching clinical significance. We previously found that myoblasts can be converted to a physiologically active neuronal phenotype by transferring a single recombinant transcription factor, REST‐VP16, which directly activates target genes of the transcriptional repressor, REST. However, the neuronal subtype of M‐RV cells and whether they can establish synaptic communication in the brain have remained unknown. M‐RV cells engineered to express green fluorescent protein (M‐RV‐GFP) had functional ion channels but did not establish synaptic communication in vitro. However, when transplanted into newborn mice cerebella, a site of extensive postnatal neurogenesis, these cells expressed endogenous cerebellar granule precursors and neuron proteins, such as transient axonal glycoprotein‐1, neurofilament, type‐III β‐tubulin, superior cervical ganglia‐clone 10, glutamate receptor‐2, and glutamate decarboxylase. Importantly, they exhibited action potentials and were capable of receiving glutamatergic synaptic input, similar to the native cerebellar granule neurons. These results suggest that M‐RV‐GFP cells differentiate into glutamatergic neurons, an important neuronal subtype, in the postnatal cerebellar milieu. Our findings suggest that although activation of REST‐target genes can reprogram myoblasts to assume a general neuronal phenotype, the subtype specificity may then be directed by the brain microenvironment. STEMCELLS2010;28:1839–1847

The rewarding effect of opioids, the driving force for compulsive behaviors of opioid abuse and addiction, is primarily mediated by the mu-opioid receptor. However, the role of the delta-opioid receptor (DOR) in opioid reward and addiction is still poorly understood. The recently discovered adaptive DOR property of exocytotic translocation in sensory neurons after chronic opioid exposure provides a new avenue of conceptual thoughts to exploring the DOR function in this psychoneurological disease. In this study, we investigated potential adaptive function of DOR in neurons of the central nucleus of the amygdala (CeA), a forebrain structure increasingly recognized for mediating stimulus reward learning in drug addiction. Using whole-cell recordings in CeA slices, we found that in rats displaying morphine-induced behavior of conditioned place preference, a behavioral measure of drug reward, the overall synaptic strength of glutamate synapses in CeA neurons was significantly enhanced. The selective DOR agonist [D-Pen(2),D-Pen(5)]-enkephalin, having no apparent effect on glutamatergic excitatory postsynaptic current (EPSC) in neurons from control rats, produced a significant, dose-dependent inhibition of the synaptic current in neurons from those morphine-treated rats. Detailed analyses of EPSC properties revealed that DOR activation inhibited the EPSC by reducing presynaptic release of glutamate, indicating functional DOR emerging on presynaptic glutamate terminals. The morphine treatment also significantly increased DOR proteins in CeA preparations of synaptosomes. These findings provide functional evidence for an adaptive modulation by presynaptic DOR of a key synaptic activity altered by morphine, thus implying likely important involvement of DOR in opioid reward and addiction.

Opioid analgesics remain the choice for the treatment of moderate to severe pain. Recent research has established that the µ-opioid receptor is predominantly responsible for mediating many opioid actions, including analgesia and opioid tolerance. However, the function of δ-opioid receptors is rather puzzling at present, with inconsistent reports of system effects by agonists of δ-opioid receptors. The functional interaction between µ-opioid receptors and δ-opioid receptors is also poorly understood. In this study, we demonstrated that in a brainstem site critically involved in opioid analgesia, agonists of δ-opioid receptors, ineffective in opioid naive rats, significantly inhibit presynaptic GABA release in the brainstem neurons from morphine-tolerant rats. In membrane preparation from control brainstem tissues, Western blot detected no proteins of δ-opioid receptors, but consistent δ-opioid receptor proteins were expressed in membrane preparation from morphine-tolerant rats. Immunohistochemical studies revealed that long-term morphine treatment significantly increases the number of δ-opioid receptor-immunoreactive varicosities that appose the postsynaptic membrane of these neurons. The colocalization of δ-opioid receptor-immunoreactive varicosities with the labeling of the GABA-synthesizing enzyme glutamic acid decarboxylase is also significantly increased. From a behavioral perspective, activation of δ-opioid receptors in the brainstem nucleus, lacking an effect in opioid naive rats, became analgesic in morphine-tolerant rats and significantly reduced morphine tolerance. These findings indicate that long-term morphine treatment induces the emergence of functional δ-opioid receptors and δ-opioid receptor-mediated analgesia, probably through receptor translocation to surface membrane in GABAergic terminals. They also suggest that opioid drugs with preference for δ-opioid receptors may have better therapeutic effect in a µ-opioid-tolerant state.

The hyperpolarization‐activated current (Ih) is important in the control of resting membrane potential, in the regulation of network firing pattern and in the modulation of presynaptic transmitter release in central neurons. Recent studies on native and cloned Ihchannels have demonstrated that the Ihchannel is commonly modulated by cAMP through a positive shift in its voltage dependence without a change in its maximum current. The present study demonstrates that activation of κ‐opioid receptors enhances Ihby increasing its maximum current in brainstem neurons in the nucleus raphe magnus. Agents that interfere with the release of intracellular calcium from calcium stores altered the maximum Ihand significantly attenuated the κ‐receptor‐mediated enhancement of Ih. These results suggest that κ‐opioid receptors enhance the maximum Ihby mobilizing intracellular calcium from calcium stores. This provides a physiological function for κ‐receptor‐stimulated calcium release and may suggest another Ih‐regulating mechanism by intracellular calcium in central neurons.

Abstract: Objective: In order to defne the common deleted region related to primary gastric carcinomas in Chinese, the frequency of loss of heterozygosit (LOH) on human chromosome 7q and its clinicai significance were investigated. Methods: A set of 9 microsatellite markers on 7q with an average genetic distance of l0cM were used to identify LOH by muiti -PCR amplification of matched tumor and non-tumor DNAs from 70 patients with primary gastric carcinoma. The PCR products were separated by electrophoresis in poiyacrylamide gels and analysed for LOH by using Genescan and Genotyper software. Results: The total frequency of LOH at any iocus on 7q was 34.3% (24/ 70) in the tumors. Compared fo non -tumor DNA, LOH at D7S486 and D7S798 loci were higher, 24.0% (12/50) and 19.2% (5/26), respectively The total frequency of LOH on 7q was markedly higher with an increase in the clinical stage (P<0.05). The frequency of LOH at D7S486 in cases with lymph node metastasis was significanty higher than in cases without lymph node metastasis,P=0.015. Conclusion: The higher incidence of LOH at O7S486 and D7S798 in primary gastric carcinoma compared to normal tissue suggests that the potential tumor suppressor genes (TSGs) involved in the progression of gastric carcinoma might be nearby these 2 locl.

While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABACeA) project to glutamatergic neurons in the parafascicular nucleus (GluPF). These GluPFneurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing. Enhanced inhibition of the GABACeA→GluPF→S2 pathway is found in mice exhibiting CP symptoms. Reversing this pathway using chemogenetic or optogenetic approaches alleviates CP symptoms. Together, the current study demonstrates the putative importance of the GABACeA→GluPF→S2 pathway in controlling at least some aspects of CP.

ABSTRACTImmunotherapy is reportedly effective in a subset of colorectal cancers (CRCs) with high microsatellite instability (MSI-H). Exploring the expression patterns and clinical values of immunologic molecules is critical in defining the specific responsive candidates. Here, we performed comprehensive molecular profiling of the B7 and TNFR family genes across 6 CRC datasets with over 1,000 patients’ details using cBioPortal TCGA data. About 20% of patients had B7 and TNFR family gene alterations. The frequency of B7 gene mutations (2.2%–5%) were similar to copy number alterations (0.53%–5.46%). TNFR amplifications were relatively more common (5.45–11.32%) than that of B7 (0.09–2.73%). B7 and TNFR gene mRNAs were upregulated in 26% of cases (102/379) and 16% of cases (61/379), respectively. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. Clinically, both B7-H3 and TNFSF7 mRNA overexpression were associated with unfavorable clinical outcomes, and the B7-H3 expression was increased gradually in cases with gene amplifications. Moreover, patients with MSI-H had significantly higher PD-L1 or PD-1 expression. Most importantly, in MSI-H group, patients with PD-L1 or PD-1 upregulation had poorer survivals than those with PD-L1/PD-1 downregulation. This is the first study drawing the immune landscapes of the co-stimulator B7 and TNFR families in CRC and showing that MSI-H patients with PD-1/PD-L1 upregulation are associated with poor clinical outcomes, providing potential markers to stratify patients responsive to immune checkpoint therapy.