Serotonin's Role in Inflammatory Signaling Pathway Modulation for Colon Cancer Suppression.

Background Neurons can be effectively regulated by serotonin and dopamine. Their role in anti-inflammatory pathways opens new doors for therapeutic research, particularly in chemotherapeutics. The present study investigated serotonin's role in suppressing inflammation and its potential anticancer effects in KERATIN-forming tumor cell line HeLa cells (KB cells).  Methods - in vitro and in silico analysis The study delved further into the molecular mechanisms by assessing the expression levels of key markers involved in inflammation and cancer progression, such as B-cell leukemia/lymphoma 2 protein (BCl-2), tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) using Real-time reverse-transcriptase-polymerase chain reaction at concentrations below the IC50 (50 and 100 µg/ml). The binding capability of serotonin (CID 5202) with glycoform of human interleukin 6 (PDB: 7NXZ) was analyzed with the help of Schrodinger molecular suites. Results The findings showcased serotonin's potent growth inhibition in KB cells, with an IC50 value of 225±3.1µg/ml. Additionally, it demonstrated a multifaceted impact by downregulating the expression of BCl-2, TNF-α, and IL-6, pivotal factors in cancer cell survival and inflammation regulation. The docking score was - 5.65 (kcal/mol) between serotonin and glycoform of Human Interleukin 6. It is bound with ASN 143 by two hydrogen bonds. Thus, molecular docking analysis showed an efficient bounding pattern. The research findings indicate that serotonin successfully blocks NF-κB pathways in KB cells, underscoring its therapeutic promise against colon cancer and offering vital information for additional clinical investigation.  Conclusion According to the study's conclusion, serotonin has a remarkable anticancer potential by effectively blocking NF-κB B pathways in KB cells, revealing its promising potential as a therapeutic agent against colon cancer. These comprehensive findings offer significant insights into serotonin's intricate molecular interactions and its profound impact on cancer-related signaling pathways, paving the way for further exploration and potential clinical applications in cancer treatment strategies.

Can environmental protection tax alleviate the mismatch of financing and investment maturities of heavily polluting enterprises?

The gradual implementation of environmental protection tax policies has incentivized enterprises to engage in green production, effectively promoting China's accelerated achievement of the "dual­carbon" goal. Although environmental protection tax has an important impact on the investment and financing decisions of heavily polluting enterprises (HPE), few studies have focused on the relationship between environmental protection tax and mismatch of financing and investment maturities. In this paper, we consider China's environmental protection tax reform as a "quasi-natural experiment", and utilize the data of A-share listed companies from 2013 to 2022, and use a difference-in-differences (DID) model to assess the impact of this policy on the degree of mismatch of financing and investment maturities of HPE. The study shows that the implementation of the environmental protection tax policy (EPTP) significantly reduces the investment and financing maturities mismatch of the HPE, but this effect "fails" in the high tax rate area, and the policy is difficult to reverse the financing difficulties of the enterprises with a large degree of their own investment and financing maturities mismatch. The mediation mechanism test proves the EPTP acts on the mismatch of financing and investment maturities through two paths: alleviating the financing constraints faced by enterprises and increasing external supervision pressure; the impact of the policy has a time-differentiated effect, which is weakened year by year.

High levels of tumor cell-intrinsic STING signaling are associated with increased infiltration of CD8+ T cells in dMMR/MSI-H gastric cancer.

Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits an immune-active tumor microenvironment (TME) compared to MMR proficient (pMMR)/microsatellite stable/Epstein-Barr virus-negative [EBV (-)] GC. The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered a key regulator of immune cell activation in the TME. However, its significance in regulating the immune-active TME in dMMR/MSI-H GC remains unclear. Here, we demonstrated that tumor cell-intrinsic cGAS-STING was highly expressed in dMMR GC compared to pMMR/EBV (-) GC. The expression of tumor cell-intrinsic STING was significantly and positively associated with the number of CD8+ tumor-infiltrating lymphocytes in GC. Analysis of TCGA datasets revealed that the expression of interferon-stimulated genes and STING downstream T-cell attracting chemokines was significantly higher in MSI-H GC compared to other subtypes of GC with EBV (-). These results suggest that tumor cell-intrinsic STING signaling plays a key role in activating immune cells in the dMMR/MSI-H GC TME and might serve as a novel biomarker predicting the efficacy of immunotherapy for GC treatment.

Validating a novel paradigm for simultaneously assessing mismatch response and frequency-following response to speech sounds.

BACKGROUND: Speech sounds are processed in the human brain through intricate and interconnected cortical and subcortical structures. Two neural signatures, one largely from cortical sources (mismatch response, MMR) and one largely from subcortical sources (frequency-following response, FFR) are critical for assessing speech processing as they both show sensitivity to high-level linguistic information. However, there are distinct prerequisites for recording MMR and FFR, making them difficult to acquire simultaneously NEW METHOD: Using a new paradigm, our study aims to concurrently capture both signals and test them against the following criteria: (1) replicating the effect that the MMR to a native speech contrast significantly differs from the MMR to a nonnative speech contrast, and (2) demonstrating that FFRs to three speech sounds can be reliably differentiated. RESULTS: Using EEG from 18 adults, we observed a decoding accuracy of 72.2% between the MMR to native vs. nonnative speech contrasts. A significantly larger native MMR was shown in the expected time window. Similarly, a significant decoding accuracy of 79.6% was found for FFR. A high stimulus-to-response cross-correlation with a 9ms lag suggested that FFR closely tracks speech sounds. COMPARISON WITH EXISTING METHOD(S): These findings demonstrate that our paradigm reliably captures both MMR and FFR concurrently, replicating and extending past research with much fewer trials (MMR: 50 trials; FFR: 200 trials) and shorter experiment time (12minutes). CONCLUSIONS: This study paves the way to understanding cortical-subcortical interactions for speech and language processing, with the ultimate goal of developing an assessment tool specific to early development.

Immune microenvironmental heterogeneity according to tumor DNA methylation phenotypes in microsatellite instability-high colorectal cancers.

The detailed association between tumor DNA methylation, including CpG island methylation, and tumor immunity is poorly understood. CpG island methylator phenotype (CIMP) is observed typically in sporadic colorectal cancers (CRCs) with microsatellite instability-high (MSI-H). Here, we investigated the differential features of the tumor immune microenvironment according to CIMP status in MSI-H CRCs. CIMP-high (CIMP-H) or CIMP-low/negative (CIMP-L/0) status was determined using MethyLight assay in 133 MSI-H CRCs. All MSI-H CRCs were subjected to digital pathology-based quantification of CD3 + /CD8 + /CD4 + /FoxP3 + /CD68 + /CD204 + /CD177 + tumor-infiltrating immune cells using whole-slide immunohistochemistry. Programmed death-ligand 1 (PD-L1) immunohistochemistry was evaluated using the tumor proportion score (TPS) and combined positive score (CPS). Representative cases were analyzed using whole-exome and RNA-sequencing. In 133 MSI-H CRCs, significantly higher densities of CD8 + tumor-infiltrating lymphocytes (TILs) were observed in CIMP-H tumors compared with CIMP-L/0 tumors. PD-L1 TPS and CPS in CIMP-H tumors were higher than in CIMP-L/0 tumors. Next-generation sequencing revealed that, compared with CIMP-L/0 tumors, CIMP-H tumors had higher fractions of CD8 + T cells/cytotoxic lymphocytes, higher cytolytic activity scores, and activated immune-mediated cell killing pathways. In contrast to CIMP-L/0 tumors, most CIMP-H tumors were identified as consensus molecular subtype 1, an immunogenic transcriptomic subtype of CRC. However, there were no differences in tumor mutational burden (TMB) between CIMP-H and CIMP-L/0 tumors in MSI-H CRCs. In conclusion, CIMP-H is associated with abundant cytotoxic CD8 + TILs and PD-L1 overexpression independent of TMB in MSI-H CRCs, suggesting that CIMP-H tumors represent a typical immune-hot subtype and are optimal candidates for immunotherapy in MSI-H tumors.

Finding the right dose: NMDAR modulating treatments for cognitive and plasticity deficits in schizophrenia and the role of pharmacodynamic target engagement.

Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are amongst the leading causes of disability in schizophrenia. Despite this, there are no FDA approved treatments for CIAS, and the development of treatments has been limited by numerous Phase II/III failures of compounds that showed initial promise in small-scale studies. N-methyl-d-aspartate-type glutamate receptors (NMDAR) have been proposed to play an important role in schizophrenia; moreover, NMDAR has a well characterized role in cognition, learning and neuroplasticity. We review prior published clinical trials in CIAS focusing on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We will use this discussion of prior studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in Phase III. A range of direct and indirect NMDAR modulators will be covered, including d-serine, d-cycloserine, memantine, glycine and "first generation" glycine transport inhibitors (GTI, e.g. sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel GTI and luvadaxistat, a D-amino acid oxidase inhibitor (DAAO-I) that increases brain d-serine levels and indirect non-invasive brain stimulation NMDAR modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery will be emphasized, including mismatch negativity (MMN), auditory steady state (ASSR) and time-frequency event-related potential (TF-ERP) approaches.

Real-world outcomes of stage II and III colorectal cancers treated by postoperative adjuvant chemotherapy based on the mismatch repair status.

PURPOSE: In Japan, immunohistochemistry for mismatch repair (MMR) proteins targeted at stage II and III colorectal cancers (CRCs) has been covered by national insurance since October, 2022. This study aimed to clarify the long-term outcomes of patients with stage II and III CRCs receiving postoperative adjuvant chemotherapy based on their MMR status. METHODS: The outcomes of 640 patients who underwent radical surgery for stage II and III CRCs were analyzed retrospectively. RESULTS: Deficient MMR (dMMR) was diagnosed in 41 (13.3%) patients with stage II and 28 (9.1%) patients with stage III CRC. The overall survival and recurrence rates were not significantly different between the patients with stage II and those with stage III CRC. The risk factors for recurrence among those with stage II CRC were tumors on the left side, T4 disease, and the presence of BRAF wild type. The recurrence rates were lower in the stage II CRC patients with sporadic dMMR than in those with suspected Lynch syndrome (LS). The first site of recurrence was more frequently the peritoneum or distant lymph node in patients with dMMR. CONCLUSIONS: Stage II CRC patients with sporadic dMMR were found to have a very good prognosis. On the other hand, peritoneal dissemination or distant lymph node metastasis tended to develop in patients with dMMR.

Glioma oncogenesis in the Constitutional mismatch repair deficiency (CMMRD) syndrome.

Background: Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas. Methods: Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma. Results: PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation. Conclusions: CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.

Native language background affects the perception of duration and pitch.

Estonian is a quantity language with both a primary duration cue and a secondary pitch cue, whereas Chinese is a tonal language with a dominant pitch use. Using a mismatch negativity experiment and a behavioral discrimination experiment, we investigated how native language background affects the perception of duration only, pitch only, and duration plus pitch information. Chinese participants perceived duration in Estonian as meaningless acoustic information due to a lack of phonological use of duration in their native language; however, they demonstrated a better pitch discrimination ability than Estonian participants. On the other hand, Estonian participants outperformed Chinese participants in perceiving the non-speech pure tones that resembled the Estonian quantity (i.e., containing both duration and pitch information). Our results indicate that native language background affects the perception of duration and pitch and that such an effect is not specific to processing speech sounds.

Amphicrine carcinoma of the right colon, a report of a case and review of literature.

Mixed neuroendocrine and non-neuroendocrine neoplasms, recently recognized in the WHO classification as (MiNEN), are rare tumors of the gastrointestinal tract. These tumors are composed of two distinct cellular components; a well- or poorly differentiated neuroendocrine tumor and a non-neuroendocrine tumor, usually in the form of an adenocarcinoma, either admixed with or adjacent to one another. A rarer phenotype is a tumor in which the endocrine and epithelial cell features occur within the same cell; i.e. amphicrine carcinoma. Herein, we report the case of an 80-year-old female patient who presented with melena, and who, on biopsy was diagnosed as amphicrine carcinoma that was mismatch repair deficient (MMRd) with loss of MLH1/PMS2 nuclear expression by immunohistochemistry. The histological and immunohistochemical findings of this rare entity are presented with review of pertinent literature.

Timing mowing for maximal energy gain - Managing foraging habitat of wintering geese under extreme drought conditions.

The availability of high-quality food resources is a critical determinant of wildlife fitness. Over the past two decades, phenological mismatch - the temporal misalignment between animals' peak nutrient demand and optimal resource availability - has emerged as a significant conservation challenge. This issue is particularly worrisome for migratory birds, which must accumulate energy reserves to meet the elevated metabolic demands of migration between breeding and wintering grounds. In Poyang Lake, a crucial wintering ground along the East Asian-Australasian flyway, increasing asynchrony between vegetation growth and the migration of herbivorous waterbirds significantly impedes conservation efforts and presents a major management challenge for this Ramsar wetland. This study evaluates the efficacy of mowing, a grassland management measure, in regulating plant growth processes and restoring food resources for geese. In-situ mowing experiments were conducted with varying timings in Carex wet meadows, the primary foraging habitats of geese. Optimal mowing times were identified, and the maximum goose carrying capacity was assessed by comparing Carex growth and nutritional dynamics with goose dietary requirements. The results reveal that mowing effectively slows down the aging process of Carex, and protein content is identified as a critical limiting factor for geese foraging. Different mowing timings extend the suitable foraging period by 11-25 days. Estimates suggest varying carrying capacities with different mowing timings, supporting goose populations ranging from 133 to 2,046 in Changhuchi Lake during wintering. The optimal mowing window is early October, avoiding dates before late September and after late November. Moreover, multiple-stage mowing is recommended to accommodate different wintering stages. The study highlights mowing as a potential habitat restoration approach for goose conservation, effectively mitigating the challenges imposed by phenological mismatch directly and indirectly caused by anthropogenic activities.

Effect of MR-guided perfusion imaging mismatch profiles within 6 h on endovascular thrombectomy outcomes.

BACKGROUND: The treatment of acute ischemic stroke (AIS) aims to achieve early vascular recanalization and reperfusion of the penumbra. However, the effect of early penumbral imaging within 6 h on clinical outcomes remains unclear. The objective of this study was to determine the effect of magnetic resonance-guided (MR-guided) perfusion imaging within 6 h after symptom onset on endovascular thrombectomy outcomes in AIS patients. METHODS: We prospectively collected the clinical information of consecutive AIS patients undergoing endovascular thrombectomy based on MR-guided perfusion imaging within 6 h after symptom onset from AISRNA and EVTRNA studies. The primary outcome was defined as the poor outcome (mRS > 2 within 90 days). The perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch was assessed by an automated software. RESULTS: We enrolled 84 patients (25 in the mismatch ≤ 1.8 group and 59 in the mismatch > 1.8 group). Significant difference was found between the mismatch > 1.8 group and the mismatch ≤ 1.8 group for the incidence of disabling stroke (mRS > 2) within 90 days (40.7% vs. 68.0%, OR: 3.099, 95% CI: 1.154-8.323, P = 0.025). Intracranial hemorrhage occurred in 8 patients (13.6%) in the mismatch > 1.8 group and 10 patients in the mismatch ≤ 1.8 group (40.0%) (P = 0.010). The risk of severe cerebral edema was 2/59 (3.4%) vs. 7/25 (28.0%) (P = 0.004). These findings remained stable after adjustment. CONCLUSIONS: MR-guided perfusion imaging mismatch profiles within 6 h after symptom onset may be feasible to predictclinical outcomes and reduce clinically ineffective reperfusion after endovascular thrombectomy.

Mismatch Negativity and P3a in Unaffected Siblings of Individuals with Autism Spectrum Disorder and the Exploration on the Neurocognitive Implications.

Evidence suggests different mismatch negativity (MMN) and P3a responses in individuals with autism spectrum disorder (ASD). Since unaffected siblings shared aberrant neurocognition and brain connectivity with ASD probands, this study investigated MMN and P3a responses in unaffected siblings and explored its neurocognitive implications and effects modifiers. We assessed 43 unaffected siblings of ASD probands and 64 non-autistic comparisons (NTC) using MMN and P3a on both frequency and duration oddball paradigms. The amplitude and latency of MMN and P3a were compared between unaffected siblings and NTC, and validated in 67 ASD probands. In addition, the neurocognitive correlates of MMN and P3a parameters were explored in attention performance, spatial working memory (SWM), and visual research via the tasks of the Conners' Continuous Performance Test and the Cambridge Neuropsychological Test Automated Battery. Compared to NTC, unaffected siblings and ASD probands presented a shorter MMN latency. The P3a amplitude of the duration paradigm (dP3a) was correlated with fewer commission errors, fewer SWM total errors, higher detectability, and more correct responses on visual search tasks. In addition, the dP3a amplitude significantly interacted with sibship, age, and full-scale IQ to predict attention performance, SWM total errors, and total correct response on visual search. Findings suggest that unaffected siblings of ASD may have earlier brain responses upon novelty discrimination. P3a amplitude may correlate with better neurocognitive performance, but the effect was moderated by sibship, age, and intelligence.

Clinical Insights and Potential Benefits of Stem Cell Transplantation for Constitutional Mismatch Repair Deficiency: A Case Report of Two Siblings.

Constitutional mismatch repair deficiency (CMMRD) syndrome, caused by biallelic mutations in mismatch repair genes, is one of the most aggressive hereditary cancer syndromes. This report presents the clinical course of two brothers diagnosed with CMMRD. The first patient was diagnosed with T-cell lymphoma at the age of three and a half years, a relapse, and synchronous glioblastoma at the age of seven and a half years. After treatment with chemotherapy and neurosurgery, haematopoietic stem cell transplant (HSCT) was performed. The second patient was diagnosed with mediastinal T-cell lymphoma at the age of two and a half years and a relapse at the age of four and a half years. He also received chemotherapy and underwent HSCT. Both patients exhibited café au lait macules (CALMs), a common but non-specific feature of CMMRD, often confused with neurofibromatosis type 1 (NF1) syndrome. This study highlights the phenotype of CMMRD syndrome, associated cancers, and the potential benefits of stem cell transplantation. Previous reports suggest that allogeneic HSCT might reduce subsequent haematological malignancies and increase survival.

Durable response to pembrolizumab in hepatic metastasis from colonic carcinoma with Lynch syndrome: a case report.

Pembrolizumab and other immunotherapies have become central in treating metastatic colon cancer, particularly effective in patients with mismatch repair deficiencies. We report a case involving a man who initially underwent radical surgery for sigmoid colon cancer on April 27, 2011, followed by hepatic tumor resection on September 21, 2017. Post-surgery, he received eight cycles of adjuvant chemotherapy with the CAPEOX regimen and was regularly monitored through CT and MRI scans. On August 24, 2022, liver metastases were detected, and he was diagnosed with Lynch syndrome (LS) due to germline mutation in the MSH2 and EPCAM genes. He commenced treatment with 200mg of pembrolizumab intravenously every three weeks on September 2, 2022, and demonstrated a sustained response. However, after 17 cycles, he developed a treatment related adverse event (TRAE) of pancreatic endocrine dysfunction, leading to type 1 diabetes, managed with subcutaneous insulin injections. After 30 cycles of treatment, no evidence of disease was observed. This case underscores the significant clinical benefits of first-line pembrolizumab in managing hepatic metastasis in colonic carcinoma associated with LS, despite the occurrence of TRAEs. It raises critical questions regarding the optimal duration of immunotherapy following a complete or partial response and whether treatment should be discontinued upon the emergency of TRAEs. Continued research and forthcoming clinical trials with checkpoint inhibitors are expected to refine treatment protocols for LS-associated carcinoma.

Efficacy and safety of PD-1/L1 inhibitors as first-line therapy for metastatic colorectal cancer: a meta-analysis.

Objective: To evaluate the efficacy and safety of PD-1/L1 inhibitors as first-line therapy in metastatic colorectal cancer(mCRC). Method: Articles evaluating first-line PD-1/L1 inhibitors for mCRC were sought in four databases (Pubmed, Embase, Web of Science, and the Cochrane Library) from the inception of the databases until 11 November 2023. Meta-analyses were conducted to assess the rates of progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR), and grade ≥ 3 treatment-related adverse events (trAEs). Results: Totally nine studies were included for meta-analysis. A subgroup analysis was performed based on mismatch repair(MMR) status and regimens. In patients diagnosed with mismatch repair-deficient(dMMR) mCRC who received PD-1/L1 inhibitors as their first-line treatment, the ORR was 0.54 (95% CI, 0.39 to 0.68), the median PFS was 53.2 months, the Grade≥ 3 TRAEs rate was 0.33(95% CI, 0.12 to 0.60) and the median OS was not determined. For patients with proficient mismatch repair (pMMR) mCRC who underwent a combined treatment of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody and chemotherapy as their first-line therapy, the ORR was 0.62 (95% CI, 0.56 to 0.68), the median PFS was 10.1 months, the median OS was 26.7 months, and the Grade≥ 3 TRAEs rate was 0.59(95% CI, 0.39 to 0.77). Conclusion: Our results revealed that the utilization of PD-1/L1 inhibitors as first-line therapy for dMMR mCRC yielded highly favorable outcomes, while maintaining an acceptable level of safety. Administering a combination of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody, and chemotherapy as first-line treatment in patients with pMMR mCRC led to an improved ORR. However, there was no significant improvement in the long-term prognosis of the tumor. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506196, identifier CRD42024506196.

Evidence for a metal disease refuge: The amphibian-killing fungus (Batrachochytrium dendrobatidis) is inhibited by environmentally-relevant concentrations of metals tolerated by amphibians.

The amphibian-killing fungus Batrachochytrium dendrobatidis (Bd) has caused substantial declines in Bd-susceptible amphibian species worldwide. However, some populations of Bd-susceptible frogs have managed to survive at existing metal-polluted sites, giving rise to the hypothesis that frogs might persist in the presence of Bd if Bd is inhibited by metals at concentrations that frogs can tolerate. We tested this hypothesis by measuring the survival of Bd zoospores, the life stage that infects amphibians, and calculated the LC50 after exposure to environmentally-relevant elevated concentrations of copper (Cu), zinc (Zn), and their combination (Cu + Zn) in two repeated 4-day acute exposure runs. We also measured the chronic sensitivity of Bd to these metals over three generations by measuring the number of colonies and live zoospores and calculating EC50 concentrations after 42 days of exposure. We then compared acute and chronic sensitivity of Bd with amphibian sensitivities by constructing species sensitivity distributions (SSDs) using LC50 and EC50 data obtained from the literature. Acute sensitivity data showed that Bd zoospore survival decreased with increasing metal concentrations and exposure durations relative to the control, with the highest LC50 values for Cu and Zn being 2.5 µg/L and 250 µg/L, respectively. Chronic exposures to metals resulted in decreased numbers of Bd colonies and live zoospores after 42 days, with EC50 values of 0.75 µg/L and 1.19 µg/L for Cu and Zn, respectively. Bd zoospore survival was 10 and 8 times more sensitive to Cu and Zn, respectively in acute, and 2 and 5 times more sensitive to Cu and Zn in chronic exposure experiments than the most sensitive amphibian species recorded. Our findings are consistent with the hypothesis that metals in existing metal-polluted sites may have a greater impact on Bd relative to amphibians' performance, potentially enabling Bd-susceptible amphibians to persist with Bd at these sites.

Transient changes in mismatch negativity after two sessions of electroconvulsive therapy for atypical psychosis: A case report.

Background: Cognitive abnormalities associated with electroconvulsive therapy (ECT) are limited to the first few days after treatment. Mismatch negativity (MMN) is an event-related potential that reflects an automatic auditory change detection process under nonattention conditions and cognitive function in psychotic disorders and may be trait- or state-dependent. This study aimed to report the changes in MMN and cognitive function after two ECT treatments in a female patient who underwent maintenance ECT for atypical psychosis. Case Presentation: A 67-year-old Japanese woman with atypical psychosis was admitted to our hospital for the maintenance of ECT. She received two ECT treatments. We measured her duration-MMN (MMN-D) at baseline, the day after two ECT treatments, and approximately 40 days after the two ECT treatments. After the two ECT treatments, the peak latency of the MMN on the following day was delayed compared with that before the first ECT treatment. Forty days after the two ECT treatments, the peak latency reverted to the baseline. The Brief Assessment of Cognition in Schizophrenia scores measured at the same time point also showed a similar temporary decrease in scores. Conclusion: Peak latency prolongation in MMN-D may reflect transient cognitive abnormalities after ECT. MMN can be useful to evaluate cognitive dysfunction, one of the adverse events of ECT. However, future studies are needed to examine the reproducibility and to examine the results in diseases other than atypical psychosis.

Enhanced Commendable Sensitivity and Specificity for MSI in Colorectal Cancer by a New PCR-HRM Based 8-Loci MSI Assay.

BACKGROUND: This study evaluated the performance of the PCR-HRM assay by comparing it with immunohistochemistry (IHC) for mismatch repair (MMR) proteins and the PCR capillary electrophoresis (PCR-CE) methods. RESULTS: A total of 224 patients with colorectal cancer participated in the study, with nearly half having mismatch repair deficiency (dMMR) tissues and the remainder possessing pMMR tissues. There was a 97.77% concordance between the PCR-HRM assay and IHC, and a 97.56% concordance between PCR-HRM and the PCR-CE assay. In comparison with IHC for dMMR proteins, the PCR-HRM demonstrated a sensitivity of 96.36% and a specificity of 99.12%. When juxtaposed with the PCR-CE assay, its sensitivity was 98.96% and specificity stood at 96.33%. The mutations observed in the microsatellite loci were uniformly distributed across all eight loci. Discrepant outcomes were more frequent in instances of MLH1 and PMS2 deficiency. Furthermore, the germline mutation status of MLH1, MSH2, PMS2, and MSH6 in 62 patients was ascertained using next-generation sequencing. All patients displaying MMR gene pathogenic mutations (N = 14) were identified as MSI-H by PCR-HRM, whereas those with MSS tissues (N = 43) did not exhibit MMR gene pathogenic mutations. Thus, the PCR-HRM method proficiently pinpoints tumors with verified germline MMR mutations, indicative of Lynch syndrome. CONCLUSION: Conclusively, the PCR-HRM assay emerges as a swift and congruent diagnostic tool for microsatellite instability, boasting commendable sensitivity and specificity in colorectal cancer.

Usefulness of synthetic MRI for differentiation of IDH-mutant diffuse gliomas and its comparison with the T2-FLAIR mismatch sign.

INTRODUCTION: The T2-FLAIR mismatch sign is a characteristic imaging biomarker for astrocytoma, isocitrate dehydrogenase (IDH)-mutant. However, investigators have provided varying interpretations of the positivity/negativity of this sign given for individual cases the nature of qualitative visual assessment. Moreover, MR sequence parameters also influence the appearance of the T2-FLAIR mismatch sign. To resolve these issues, we used synthetic MR technique to quantitatively evaluate and differentiate astrocytoma from oligodendroglioma. METHODS: This study included 20 patients with newly diagnosed non-enhanced IDH-mutant diffuse glioma who underwent preoperative synthetic MRI using the Quantification of Relaxation Times and Proton Density by Multiecho acquisition of a saturation-recovery using Turbo spin-Echo Readout (QRAPMASTER) sequence at our institution. Two independent reviewers evaluated preoperative conventional MR images to determine the presence or absence of the T2-FLAIR mismatch sign. Synthetic MRI was used to measure T1, T2 and proton density (PD) values in the tumor lesion. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance. RESULTS: The pathological diagnoses included astrocytoma, IDH-mutant (n = 12) and oligodendroglioma, IDH-mutant and 1p/19q-codeleted (n = 8). The sensitivity and specificity of T2-FLAIR mismatch sign for astrocytoma were 66.7% and 100% [area under the ROC curve (AUC) = 0.833], respectively. Astrocytoma had significantly higher T1, T2, and PD values than did oligodendroglioma (p < 0.0001, < 0.0001, and 0.0154, respectively). A cutoff lesion T1 value of 1580 ms completely differentiated astrocytoma from oligodendroglioma (AUC = 1.00). CONCLUSION: Quantitative evaluation of non-enhanced IDH-mutant diffuse glioma using synthetic MRI allowed for better differentiation between astrocytoma and oligodendroglioma than did conventional T2-FLAIR mismatch sign. Measurement of T1 and T2 value by synthetic MRI could improve the differentiation of IDH-mutant diffuse gliomas.