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Abstract Positive peritoneal washing cytology is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC); however, its sensitivity is relatively low. This study evaluated the performance of peptide nucleic acid (PNA)-directed PCR clamping as a molecular-based peritoneal washing cytology for sensitive detection of KRAS mutation in PDAC. Intraoperative peritoneal washing fluid (IPWF) obtained from patients with PDAC who underwent surgery was analyzed. PNA-directed PCR clamping was performed on DNA extracted from IPWF. Among 54 patients enrolled, threshold cycle (Ct) was significantly lower in patients with positive peritoneal washing cytology than in those with negative peritoneal washing cytology (P

Objectives: To compare the characteristics and prognosis of patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) with pleuroparenchymal fibroelastosis (PPFE) with those of patients with nodular/bronchiectatic (NB) and fibrocavitary (FC) NTM-PD. Methods: This multicenter, retrospective, observational study enrolled 32 patients with NTM-PPFE (median age: 70.5 years, 15 females) from six institutions in Japan from January 2003 to December 2018. Their clinical characteristics and response to therapy were compared with age- and sex-matched cohorts of patients with noncavitary NB and cavitary NB/FC NTM-PD. Results: Patients with NTM-PPFE had a lower body mass index and a higher standard NTM-PD therapy initiation rate than patients with other NTM-PD types. Sputum culture conversion rates were comparable between groups; however, patients with NTM-PPFE had a higher incidence of treatment-related adverse events, including optic neuropathy associated with high-dose ethambutol therapy, lower percent predicted forced vital capacity values, higher serum Krebs von den Lungen-6 (KL-6) levels, and poorer treatment outcomes than the other groups. Cox regression revealed that NTM-PPFE was an independent risk factor for death/pneumothorax (adjusted hazard ratio: 35.3, 95% confidence interval: 3.90-4692). Conclusion: NTM-PPFE is a unique NTM-PD phenotype with a poorer prognosis than the NB and FC phenotypes.

Abstract Evaluating reciprocal inhibition of the thigh muscles is important to investigate the neural circuits of locomotor behaviors. However, measurements of reciprocal inhibition of thigh muscles using spinal reflex, such as H‐reflex, have never been systematically established owing to methodological limitations. The present study aimed to clarify the existence of reciprocal inhibition in the thigh muscles using transcutaneous spinal cord stimulation (tSCS). Twenty able‐bodied male individuals were enrolled. We evoked spinal reflex from the biceps femoris muscle (BF) by tSCS on the lumber posterior root. We examined whether the tSCS‐evoked BF reflex was reciprocally inhibited by the following conditionings: (1) single‐pulse electrical stimulation on the femoral nerve innervating the rectus femoris muscle (RF) at various inter‐stimulus intervals in the resting condition; (2) voluntary contraction of the RF; and (3) vibration stimulus on the RF. The BF reflex was significantly inhibited when the conditioning electrical stimulation was delivered at 10 and 20 ms prior to tSCS, during voluntary contraction of the RF, and during vibration on the RF. These data suggested a piece of evidence of the existence of reciprocal inhibition from the RF to the BF muscle in humans and highlighted the utility of methods for evaluating reciprocal inhibition of the thigh muscles using tSCS.

Abstract Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post‐operative survival outcomes. To test this hypothesis, we utilised a multi‐institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease‐free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively (ptrend

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.

Abstract Objectives The CD274 (programmed cell death 1 ligand 1, PD‐L1)/PDCD1 (programmed cell death 1, PD‐1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence also supports an immunosuppressive effect of Fusobacterium nucleatum. We hypothesised that tumor CD274 overexpression might be inversely associated with abundance of F. nucleatum in colorectal carcinoma. Methods We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative PCR in 812 cases among 4465 incident rectal and colon cancer cases that had occurred in two prospective cohort studies. Multivariable logistic regression analyses with inverse probability weighting were used to adjust for selection bias because of tissue data availability and potential confounders including microsatellite instability status, CpG island methylator phenotype, LINE‐1 methylation level and KRAS, BRAF and PIK3CA mutations. Results Fusobacterium nucleatum DNA was detected in tumor tissue in 109 (13%) cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue (P = 0.0077). For one category‐unit increase in three ordinal F. nucleatum categories (negative vs. low vs. high), multivariable‐adjusted odds ratios (with 95% confidence interval) of the low, intermediate and high CD274 categories (vs. negative) were 0.78 (0.41–1.51), 0.64 (0.32–1.28) and 0.50 (0.25–0.99), respectively (Ptrend = 0.032). Conclusions Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting that different immunosuppressive mechanisms (i.e. PDCD1 immune checkpoint activation and tumor F. nucleatum enrichment) tend to be used by different tumor subgroups.

Functional electrical stimulation (FES), a method for inducing muscle contraction, has been successfully used in gait rehabilitation for patients with deficits after neurological disorders and several clinical studies have found that it can improve gait function after stroke and spinal cord injury. However, FES gait training is not suitable for patients with walking difficulty, such as those with severe motor paralysis of the lower limbs. We have previously shown that action observation combined with motor imagery (AO + MI) of walking induces walking-related cortical activity. Therefore, we combined FES, which alternately generates dorsiflexion and plantar flexion, with AO + MI as an alternative to gait training. The present study investigates the transient effects of 20-min of FES simultaneously with and without AO + MI of walking on corticospinal and spinal reflex excitability in able-bodied participants. We measured motor evoked potentials and Hoffmann-reflexes to assess corticospinal and spinal reflex excitability at rest before and after the 20-min FES with and without the AO + MI. Our results show that FES without AO + MI did not change excitability (p > 0.05), while FES with AO + MI facilitated corticospinal excitability (p < 0.05). This facilitation likely occurred due to the synchronization of sensory inputs from FES and cortical activity during AO + MI. Facilitation was observed only in the dorsiflexor but not the plantar flexor muscle (p < 0.05), suggesting muscle specificity of the facilitation. These results demonstrate the effectiveness of combining FES with AO + MI and pave the way for novel neurorehabilitation strategies for patients with neurological gait deficits.

Abstract Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer.

Abstract Background The portal vein is occasionally invaded by advanced malignant tumors in the pancreatic head region. However, pancreatic cancer rarely has portal vein tumor thrombi. We report a case of pancreatic cancer with a massive portal vein tumor thrombus undergoing pancreatoduodenectomy with combined resection of the portal vein. Case presentation A 71-year-old man visited a clinic with complaints of abdominal discomfort and vomiting. Gastroscopy showed a massive tumor in the duodenum. He was referred to our hospital for further examinations and treatment. The CT showed a low-density tumor with a maximum diameter of 10 cm located on the pancreas head. A tumor widely invaded the duodenum and had a 6-cm portal vein tumor thrombus. MRCP did not show obvious stenosis of the pancreatic duct due to tumor invasion. There were no findings suggesting distant metastases. Biopsy of the duodenum revealed adenocarcinoma. He was diagnosed with primary pancreatic cancer or duodenal cancer with portal vein tumor thrombus and underwent pancreatoduodectomy with resection and reconstruction of the portal vein. He suffered no postoperative complications and was discharged 2 months after surgery. The final histopathological diagnosis was pancreatic colloid carcinoma. He received adjuvant chemotherapy, but died 16 months after surgery. Conclusions Colloid carcinoma of the pancreas is rare, and pancreatic carcinoma seldom forms a portal vein tumor thrombus. We experienced a very rare case of pancreatic colloid carcinoma with portal vein tumor thrombus and performed radical resection of the pancreas and portal vein.

Abstract Background Synovial sarcoma is a soft tissue malignancy that frequently affects the extremities, adjacent to the large joints. Synovial sarcoma has a high rate of distant metastasis; however, pancreatic metastasis is extremely rare, and to our knowledge, there has been no report of bleeding due to spontaneous tumor rupture. This study reports the case of a patient with synovial sarcoma pancreatic metastasis causing tumor rupture and bleeding, which was successfully managed with emergent distal pancreatectomy. Case presentation A 27-year-old woman underwent extensive resection of the primary tumor and partial lung resection after chemotherapy for left femoral synovial sarcoma and multiple lung metastases 4 years prior. During the follow-up, a 35-mm tumor was noted in the pancreatic tail on abdominal computed tomography (CT), and no other distant metastases were detected via positron emission tomography CT. Laparoscopic distal pancreatectomy was scheduled for pancreatic metastasis of synovial sarcoma. However, before the scheduled pancreatectomy could be conducted, the patient visited the emergency department because of abdominal pain that occurred after consuming a small amount of alcohol, and CT showed ascites with high CT values and leakage of contrast media. She was diagnosed with intra-abdominal hemorrhage due to a ruptured metastatic pancreatic tumor, and an emergency operation was performed. In total, 1500 mL of blood was evacuated from the abdomen, and the bleeding pancreatic tail tumor was resected. Histopathological findings revealed synovial sarcoma metastasis and a ruptured tumor capsule, and tumor cells were observed in the hematoma. After discharge on postoperative day 18, the patient was carefully monitored and confirmed to be in relapse-free survival, without chemotherapy, at 6 months post-surgery. Conclusions While the rate of tumor growth varies depending on the grade of the tumor, the possibility of rupture should be considered even in metastatic pancreatic tumors. In the case of pancreatic tumor rupture with stable circulation, radiological evaluation for oncology is necessary, and primary resection may be compatible with resectable cases.

Abstract Background The Response Evaluation Criteria in Solid Tumors (RECIST) for computed tomography (CT) is preoperatively used to evaluate therapeutic effects. However, it does not reflect the pathological treatment response (PTR) of pancreatic ductal adenocarcinoma (PDAC). The Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for positron emission tomography (PET)/CT is effective in other cancers. This study aimed to confirm the usefulness of PERCIST and the prognostic utility of PET/CT for PDAC. Methods Forty‐two consecutive patients with PDAC who underwent neoadjuvant therapy (NAT) and pancreatectomy at our institution between 2014 and 2018 were retrospectively analyzed. We evaluated the treatment response and prognostic significance of PET/CT parameters and other clinicopathological factors. Results Twenty‐two patients who underwent PET/CT both before and after NAT with the same protocol were included. RECIST revealed stable disease and partial response in 20 and 2 cases, respectively. PERCIST revealed stable metabolic disease, partial metabolic response, and complete metabolic response in 8, 9, and 5 cases, respectively. The PTR was G3, G2, and G1 in 8, 12, and 2 cases, respectively. For comparing the concordance rates between PTR and each parameter, PERCIST (72.7% [16/22]) was significantly superior to RECIST (36.4% [8/22]) (P = .017). The area under the curve survival values of PET/CT parameters were 0.777 for metabolic tumor volume (MTV), 0.500 for maximum standardized uptake value, 0.554 for peak standardized uptake value corrected for lean body mass, and 0.634 for total lesion glycolysis. A 50% cut‐off value for the MTV reduction rate yielded the largest difference in survival between responders and nonresponders. On multivariate analysis, MTV reduction rates

Action observation (AO) and motor imagery (MI) are used for the rehabilitation of patients who face difficulty walking. Rehabilitation involving AO, MI, and AO combined with MI (AO+MI) facilitates gait recovery after neurological disorders. However, the mechanism by which it positively affects gait function is unclear. We previously examined the neural mechanisms underlying AO and MI of walking, focusing on AO+MI and corticospinal and spinal motor neuron excitability, which play important roles in gait function. Herein, we investigated the effects of a short intervention using AO+MI of walking on the corticospinal and spinal motor neuron excitability and MI ability of participants. Twelve healthy individuals participated in this study, which consisted of a 20 min intervention. Before the experiment, we measured MI ability using the Vividness of Movement Imagery Questionnaire-2 (VMIQ-2). We used motor evoked potential and F-wave measurements to evaluate the corticospinal and spinal motor neuron excitability at rest, pre-intervention, 0 min, and 15 min post-intervention. We also measured corticospinal excitability during MI of walking and the participant's ability to perform MI using a visual analog scale (VAS). There were no significant changes in corticospinal and spinal motor neuron excitability during and after the intervention using AO+MI (p>0.05). The intervention temporarily increased VAS scores, thus indicating clearer MI (p0.05). Furthermore, there was no significant correlation between the VMIQ-2 and VAS scores and changes in corticospinal and spinal motor neuron excitability. Therefore, one short intervention using AO+MI increased MI ability in healthy individuals; however, it was insufficient to induce plastic changes at the cortical and spinal levels. Moreover, the effects of intervention using AO+MI were not associated with MI ability. Our findings provide information about intervention using AO+MI in healthy individuals and might be helpful in planning neurorehabilitation strategies.

ObjectiveOur aim is to determine the strong predictors of the onset of instrumental activities of daily living (IADL) decline in community-dwelling older people.DesignA prospective cohort study with a two-year follow-up.SettingKashiwa City, Chiba Prefecture, Japan and Toshima Ward, Tokyo Metropolitan, Japan.ParticipantsThe data were acquired from two cohorts. The final sample comprised 1,523 community-dwelling older people aged 65-94 years (681 men, 842 women). They were individuals who were independent in IADL at baseline and participated in follow-up IADL assessments two years later.MeasurementsAt baseline, comprehensive assessments were performed including: health interview, gait function, hand-grip strength, skeletal muscle mass, balance function, oral function, dietary lifestyle, cognitive function, quality of life, mental status, and social network. When the two-year follow-up was performed, IADL declines were observed in 53 out of 1,523 people. The association of each Z-transformed parameter with the occurrence of IADL decline was examined by employing a binominal logistic regression model adjusting for age, gender, body weight, body height, and medical history. An odds ratio (OR) and a 95% confidence interval were calculated and compared between different parameters.ResultsA decrease in walking speed and one-legged stance time, whereas an increased timed up & go test time was associated with significant ORs for the occurrence of IADL decline.ConclusionGait-related parameters appear to be the strong predictors of the onset of IADL decline in community-dwelling older people.

Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm−1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm−1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance.

Rationale: Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Objectives: Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Methods: Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA in situ hybridization and immunohistochemistry, identified proximal and distal bronchioles in excised NCFB lungs. RNA in situ hybridization and immunohistochemistry assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial cultures tested IL-1α and IL-1β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas per section area were increased in proximal, but not distal, bronchioles in NCFB versus control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated nonectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1β-expressing macrophages. NCFB sterile sputum supernatants induced human bronchial epithelial MUC5B and MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, and IL-1β-producing macrophages in mucus plugs and downregulation of epithelial ciliogenesis genes. Conclusions: NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia. [ABSTRACT FROM AUTHOR]

Abstract Background We aimed to evaluate the efficacy and safety of 5-fluorouracil-based neoadjuvant chemoradiotherapy (NACRT) in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC). Methods This retrospective study investigated the clinicopathological features and > 5-year survival of patients with T3/T4 PDAC who underwent NACRT at our institute between 2003 and 2012. Results Seventeen resectable and eight borderline resectable patients were included. The protocol treatment completion and resection rates were 92.0% and 68.0%, respectively. Two patients failed to complete chemotherapy owing to cholangitis or anorexia. Common grade 3 toxicities included anorexia (12%), neutropenia (4%), thrombocytopenia (4%), anemia (4%), and leukopenia (12%). Pathologically negative margins were achieved in 94.1% of patients who underwent pancreatectomy. Pathological response according to Evans’ classification was grade IIA in 10 patients (58.8%), IIB in 5 patients (29.4%), and IV in 2 patients (11.8%). Postoperative pancreatic fistulas were observed in four patients (23.5%), delayed gastric emptying in one patient (5.9%), and other operative morbidities in four patients (23.5%). The 1-, 2-, 5-, and 10-year overall survival rates were 73.9%, 60.9%, 60.9%, and 39.1%, respectively (median follow-up period, 80.3 months). Conclusions NACRT is tolerable and beneficial for resectable/borderline resectable PDAC, even in the long-term.

A prognostic system for acute liver failure (ALF) with a higher predictive value is urgently needed. The role of extracellular matrix (ECM) remodeling in ALF has not been fully elucidated. We hypothesized that serologic fibrosis markers, which reflect ECM remodeling, are predictive of ALF outcome at first presentation. This observational study included 110 patients with acute liver dysfunction, of which 73 had non‐acetaminophen‐associated ALF (NAA‐ALF). We evaluated serum levels of hyaluronic acid, 7S domain of type IV collagen (4COL7S), and Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein at first presentation to a tertiary center. Serologic fibrosis markers were significantly higher in NAA‐ALF compared with acute hepatitis. Elevated hyaluronic acid and 4COL7S levels at first presentation correlated significantly with worse clinical outcomes. 4COL7S, along with age, ammonia, and the Model for End‐Stage Liver Disease (MELD) score, was a significant prognostic factor in multivariate analysis; 4COL7S correlated significantly with coagulopathy, decreased hepatic synthetic functions, advanced hepatic encephalopathy, and liver atrophy and also predicted 180‐day transplant‐free survival. Cox regression models incorporating 4COL7S with the MELD system had profoundly improved predictive values that significantly surpassed the MELD system alone. Conclusion: Elevation of serologic fibrosis markers reflecting ECM remodeling in NAA‐ALF predicted a worse clinical outcome. Incorporation of 4COL7S at first presentation to a transplant center improves the specificity while retaining the sensitivity of the MELD system. External validation of a fibrosis marker as part of a clinical prediction tool in ALF warrants further investigation.

Action observation (AO) and motor imagery (MI) are motor simulations which induce cortical activity related to execution of observed and imagined movements. Neuroimaging studies have mainly investigated where the cortical activities during AO and MI of movements are activated and if they match those activated during execution of the movements. However, it remains unclear how cortical activity is modulated; in particular, whether activity depends on observed or imagined phases of movements. We have previously examined the neural mechanisms underlying AO and MI of walking, focusing on the combined effect of AO with MI (AO+MI) and phase dependent modulation of corticospinal and spinal reflex excitability. Here, as a continuation of our previous studies, we investigated cortical activity depending on gait phases during AO and AO+MI of walking by using electroencephalography (EEG); 64-channel EEG signals were recorded in which participants observed walking with or without imagining it, respectively. EEG source and spectral analyses showed that, in the sensorimotor cortex during AO+MI and AO, the alpha and beta power were decreased, and power spectral modulations depended on walking phases. The phase dependent modulations during AO+MI, but not during AO, were like those which occur during actual walking as reported by previous walking studies. These results suggest that combinatory effects of AO+MI could induce parts of the phase dependent activation of the sensorimotor cortex during walking even without any movements. These findings would extend understanding of the neural mechanisms underlying walking and cognitive motor processes and provide clinically beneficial information towards rehabilitation for patients with neurological gait dysfunctions.

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that PIK3CA mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed PIK3CA mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, KRAS and BRAF mutations. PIK3CA mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22–2.75; P = .004]. PIK3CA mutation was statistically-insignificantly (P = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03–2.31). PIK3CA-mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than PIK3CA-wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) (P = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.

Aberrant protein glycosylation is one of the most notable features in cancerous tissues, and thereby glycoproteins with disease-relevant glycosylation alterations are fascinating targets for the development of biomarkers and therapeutic agents. For this purpose, a reliable strategy is needed for the analysis of glycosylation alterations occurring on specific glycoproteins during the progression of cancer. Here, we propose a bilateral approach combining lectin microarray-based tissue glycomic profiling and database-derived transcriptomic datasets. First, lectin microarray was used to perform differential glycomic profiling of crude extracts derived from non-tumor and tumor regions of frozen tissue sections from pancreatic ductal adenocarcinoma (PDAC). This analysis revealed two notable tissue glycome alterations in PDAC samples: increases in sialylated glycans and bisecting N-acetylglucosamine and a decrease in ABO blood group antigens. To examine aberrations in the glycosylation machinery related to these glycomic alterations, we next employed public datasets of gene expression profiles in cancerous and normal pancreases provided by The Cancer Genome Atlas and the Genotype-Tissue Expression projects, respectively. In this analysis, glycosyltransferases responsible for the glycosylation alterations showed aberrant gene expression in the cancerous tissues, consistent with the tissue glycomic profiles. The correlated alterations in glycosyltransferase expression and tissue glycomics were then evaluated by differential glycan profiling of a membrane N-glycoprotein, basigin, expressed in tumor and non-tumor pancreatic cells. The focused differential glycomic profiling for endogenous basigin derived from non-tumor and cancerous regions of PDAC tissue sections demonstrated that PDAC-relevant glycan alterations of basigin closely reflected the notable features in the disease-specific alterations in the tissue glycomes. In conclusion, the present multi-omics strategy using public transcriptomic datasets and experimental glycomic profiling using a tiny amount of clinical specimens successfully demonstrated that basigin is a representative N-glycoprotein that reflects PDAC-related aberrant glycosylations. This study indicates the usefulness of large public data sets such as the gene expression profiles of glycosylation-related genes for evaluation of the highly sensitive tissue glycomic profiling results. This strategy is expected to be useful for the discovery of novel glyco-biomarkers and glyco-therapeutic targets.

Abstract Background Previous approaches to defining subtypes of colorectal carcinoma (CRC) and other cancers based on transcriptomes have assumed the existence of discrete subtypes. We analyze gene expression patterns of colorectal tumors from a large number of patients to test this assumption and propose an approach to identify potentially a continuum of subtypes that are present across independent studies and cohorts. Results We examine the assumption of discrete CRC subtypes by integrating 18 published gene expression datasets and > 3700 patients, and contrary to previous reports, find no evidence to support the existence of discrete transcriptional subtypes. Using a meta-analysis approach to identify co-expression patterns present in multiple datasets, we identify and define robust, continuously varying subtype scores to represent CRC transcriptomes. The subtype scores are consistent with established subtypes (including microsatellite instability and previously proposed discrete transcriptome subtypes), but better represent overall transcriptional activity than do discrete subtypes. The scores are also better predictors of tumor location, stage, grade, and times of disease-free survival than discrete subtypes. Gene set enrichment analysis reveals that the subtype scores characterize T-cell function, inflammation response, and cyclin-dependent kinase regulation of DNA replication. Conclusions We find no evidence to support discrete subtypes of the CRC transcriptome and instead propose two validated scores to better characterize a continuity of CRC transcriptomes.

Transcutaneous electrical stimulation is a relatively new technique to evoke spinal reflexes in lower limb muscles. The advantage of this technique is that the spinal reflex responses can be obtained from multiple lower limb muscles simultaneously. However, repeatability of spinal reflexes evoked by transcutaneous spinal cord stimulation between days has not been evaluated. We aimed to examine repeatability of recruitment properties of the spinal reflexes evoked by transcutaneous spinal cord stimulation. Recruitment curves of the spinal reflexes evoked by transcutaneous spinal cord stimulation of 8 lower limb muscles (i.e., foot, lower leg, and thigh muscles) of 20 males were measured on two consecutive days. To confirm that responses were caused by activation of the sensory fiber, a double-pulse stimulation with 50 ms inter-pulse interval was delivered. Peak-to-peak amplitude of the first response was calculated for each muscle when no response was observed in the second response owing to post-activation depression. For comparison with the spinal reflexes evoked by transcutaneous spinal cord stimulation, the recruitment curves of the H-reflex amplitude of the soleus of 9 males were measured. Threshold intensity and maximal slope of the recruitment curves were calculated, and inter-day repeatability of the properties was quantified using intraclass correlation coefficients. For the spinal reflexes evoked by transcutaneous spinal cord stimulation, the intraclass correlation coefficient values of threshold intensity and maximal slope for each muscle ranged from 0.487 to 0.874 and from 0.471 to 0.964, respectively. Regarding the soleus H-reflex, the intraclass correlation coefficients of threshold intensity and maximal slope were 0.936 and 0.751, respectively. The present data showed that repeatability of the recruitment properties of the spinal reflexes evoked by transcutaneous spinal cord stimulation in the lower limb was moderate to high. Measurement of the spinal reflexes evoked by transcutaneous spinal cord stimulation would be useful for longitudinal neurophysiological studies.

Action observation (AO) and motor imagery (MI) are useful techniques in neurorehabilitation. Previous studies have reported that AO and MI facilitate corticospinal excitability only in those muscles that are active when actually performing the observed or imagined movements. However, it remained unclear whether spinal reflexes modulate multiple muscles simultaneously. The present study focused on AO and MI of walking and aimed to clarify their effects on spinal reflexes in lower-limb muscles that are recruited during actual walking. Ten healthy males participated in the present study. Spinal reflex parameters evoked by transcutaneous spinal cord stimulation were measured from five lower-limb muscles during rest, AO, and AO combined with MI (AO + MI) conditions. Our results showed that spinal reflexes were increased in the tibialis anterior and biceps femoris muscles during AO and in the tibialis anterior, soleus, and medial gastrocnemius muscles during AO + MI, compared with resting condition. Spinal reflex parameters in the vastus medialis muscle were unchanged. These results indicate the muscle-specific modulations of spinal reflexes during AO and AO + MI. These findings reveal the underlying neural activities induced by AO, MI, and their combined processes.