Characterizing and forecasting neoantigens-resulting from MUC mutations in COAD.

BACKGROUND: The treatment for colon adenocarcinoma (COAD) faces challenges in terms of immunotherapy effectiveness due to multiple factors. Because of the high tumor specificity and immunogenicity, neoantigen has been considered a pivotal target for cancer immunotherapy. Therefore, this study aims to identify and predict the potential tumor antigens of MUC somatic mutations (MUCmut) in COAD. METHODS: Three databases of TCGA, TIMER2.0, and cBioPortal were used for a detailed evaluation of the association between MUCmut and multi-factors like tumor mutation burden (TMB), microsatellite instability (MSI), prognosis, and the tumor microenvironment within the context of total 2242 COAD patients. Next, TSNAdb and the differential agretopicity index (DAI) were utilized to predict high-confidence neopeptides for MUCmut based on 531 COAD patients' genomic information. DAI was calculated by subtraction of its predicted HLA binding affinity of the MUCmut peptide from the corresponding wild-type peptide. RESULTS: The top six mutation frequencies (14 to 2.9%) were from MUC16, MUC17, MUC5B, MUC2, MUC4 and MUC6. COAD patients with MUC16 and MUC4 mutations had longer DFS and PFS. However, patients with MUC13 and MUC20 mutations had shorter OS. Patients with the mutation of MUC16, MUC5B, MUC2, MUC4, and MUC6 exhibited higher TMB and MSI. Moreover, these mutations from the MUC family were associated with the infiltration of diverse lymphocyte cells and the expression of immune checkpoint genes. Through TSNAdb 1.0/NetMHCpan v2.8, 452 single nucleotide variants (SNVs) of MUCmut peptides were identified. Moreover, through TSNAdb2.0/NetMHCpan v4.0, 57 SNVs, 1 Q-frame shift (TS), and 157 short insertions/deletions (INDELs) of MUCmut were identified. Finally, 10 high-confidence neopeptides of MUCmut were predicted by DAI. CONCLUSIONS: Together, our findings establish the immunogenicity and therapeutic potential of mutant MUC family-derived neoantigens. Through combining the tools of TSNAdb and DAI, a group of novel MUCmut neoantigens were identified as potential targets for immunotherapy.

Progress of near-infrared-II fluorescence in precision diagnosis and treatment of colorectal cancer.

Colorectal cancer is a malignant tumour with high incidence and mortality worldwide; therefore, improving the early diagnosis of colorectal cancer and implementing a targeted "individualized treatment" strategy is of great concern. NIR-II fluorescence imaging is a large-depth, high-resolution optical bioimaging tool. Around the NIR-II window, researchers have developed a variety of luminescent probes, imaging systems, and treatment methods with colorectal cancer targeting capabilities, which can be visualized and image-guided in clinical surgery. This article aims to overcome the difficulties in diagnosing and treating colorectal cancer. The present review summarizes the latest results on using NIR-II fluorescence for targeted colorectal cancer imaging, expounds on the application prospects of NIR-II optical imaging for colorectal cancer, and discusses the imaging-guided multifunctional diagnosis and treatment platforms.

Establishment and validation of clinical prediction model for hemorrhoid recurrence after procedure for prolapse and hemorrhoids.

This study aimed to establish a clinical model to predict the risk of hemorrhoid recurrence after procedure for prolapse and hemorrhoids. The clinical data of patients who underwent stapler hemorrhoidal mucosal circumcision in Shanxi Bethune Hospital from April 2014 to June 2017 were collected retrospectively and followed up regularly after the operation. Finally, 415 patients were included, which were divided into training group (n = 290) and verification group (n = 125). Logistic regression method was used to select meaningful predictors. The prediction model was constructed with nomographs, and the model was evaluated with correction curve, receiver operating characteristic curve and C index. The decision analysis curve was used to determine the clinical utility of the nomogram. Birth history, muscle attachment, postoperative anal urgency, anal resting pressure, postoperative nutritional index, body mass index, Wexner score, and hemorrhoid grading were included in the nomogram. The area under the curve of the prediction model was 0.813 and 0.679, respectively, in the training and verification groups, and 0.839 and 0.746, respectively, for the 5-year recurrence rate. The C index (0.737) and clinical decision curve showed that the model had high clinical practical value. The prediction model of hemorrhoid recurrence risk after hemorrhoidectomy based on multiple clinical indicators can be used for individualized prediction of hemorrhoid recurrence in patients after hemorrhoidectomy, and early intervention measures can be given to individuals with a high recurrence risk to reduce the risk of recurrence.

Detection Rate and Prognosis of Lymph Nodes in Gastric Cancer Using Nano Carbon Combined with In Vitro Anatomical Sorting.

In this study, we are going to investigate the effect of nano carbon combined with ex vitro anatomical sorting on the detection rate of lymph nodes (LNs) in gastric cancer (GC) along with the analysis of the correlation between LNs detection rate and patients' prognosis. The clinical data of patients undergoing radical gastrectomy in Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University from January 2018 to January 2019 were examined retrospectively. According to whether they adopt nano carbon tracing and specimen sorting method, patients were divided into nano carbon and control groups. The respective rate of detection and correlation of total and positive LNs, respectively, clinical treatment, tumor marker level, and long-term prognosis were matched between these groups. At the same time, the effects of the nano carbon tracer on the detection of total and positive LNs were evaluated. In nano carbon group, more LN specimens could be detected, and the number of positive LNs increased significantly. In addition, in patients with different infiltration stages and LN substations, more LNs could be detected in the nano carbon group for examination, and the detection rate of LNs with diameter less than 5 mm was also more. Furthermore, LNs (preferably positive in number) were correlated positively with the attained LNs number. Otherwise, the use of nano carbon suspension could better label LNs in each substation, especially N1 station, and improve micro-LN detection rate. At the same time, the positive metastasis rate in black-stained LNs was higher (31.67% vs. 13.51%). In relation to the clinical prognosis, CEA's level, i.e., CA199 and CA125, in the nano carbon group is controlled more effectively. Their condition was not easy to progress and relapse, and their mortality was further reduced. As a result, nano carbon, coupled with ex vitro anatomical sorting, may considerably enhance the detection rate of total and positive LNs, thereby improving the accuracy of clinical staging in GC patients, which has a good influence on their long-term prognosis.

[Early versus traditional postoperative oral feeding in patients undergoing elective colorectal surgery: a meta-analysis of safety and efficacy].

OBJECTIVE: To compare the outcomes of early oral feeding (EOF) and the traditional oral feeding (TOF) in postoperative patients with colorectal cancer using Meta-analysis. METHODS: The databases of PubMed, SCI, Ovid, The Cochrane Library, CNKI, CBM, VIP and Wanfang Data were searched to collect randomized controlled trial (RCT) about EOF versus TOF in patients undergoing elective colorectal surgery. The retrieval time span was from inception to June 1, 2016. The studies were screened according to the inclusion and exclusion criteria. The data were extracted and the quality was evaluated by 2 reviewers independently. The Meta-analysis was conducted using RevMan 5.2 software. RESULTS: A total of 14 studies with 1 807 patients (906 cases in EOF group and 901 cases in TOF group) were included. The time to first passage of flatus (MD=-16.11 h, 95%CI:-18.27 to -13.94 h, P=0.00), postoperative hospital stay (MD=-1.92 d, 95%CI:-2.83 to -1.01 d, P=0.00), hospitalization cost (ten thousand yuan) (MD=-0.58, 95%CI:-0.71 to -0.46, P=0.00) were less in EOF group compared to TOF group. EOF patients had lower total complication rate (OR=0.68, 95%CI:0.48 to 0.95, P=0.03), in which the pulmonary infection (OR=0.27, 95%CI:0.13 to 0.53, P=0.00), pharyngolaryngitis (OR=0.06, 95%CI:0.04 to 0.11, P=0.00) were lower than those in TOF group, while the tube reinsertion (OR=2.34, 95%CI:1.08 to 5.07, P=0.03) was higher. The incidence of anastomotic leakage, nausea, vomiting, abdominal distension, diarrhea, and wound infection between two groups was not significantly different(all P>0.05). There was no significant difference between two groups in IgM (P>0.05), while the IgA (MD=0.3, 95%CI:0.12 to 0.48, P=0.00), IgG (MD=2.13 ,95%CI:0.82 to 3.44, P=0.001), CD4+ (MD=3.80, 95%CI:2.55 to 5.04, P=0.00), CD4+/CD8+ (MD=0.22, 95%CI:0.04 to 0.41, P=0.02) in EOF group were higher than those in TOF group. Postoperative CRP decreased rapidly in EOF group (MD=-30.10, 95%CI:-48.07 to -12.13, P=0.00), and IL-6 was not significantly different (P>0.05). EOF patients had higher serum albumin level 5 days after operation (MD=3.27, 95%CI: 2.48 to 4.07, P=0.00). CONCLUSIONS: EOF can promote gas passage and defecation, reduce postoperative hospital stay and treatment costs. Also, it can decrease the incidence of complications and postoperative inflammation, and maintain immune function.

Two Rare Cases Involving the Spread of Tuberculosis: A Tuberculous Abscess of the Chest Wall Invading the Liver by Way of the Diaphragm.

We herein report two separate cases in which a tuberculous abscess of the chest wall invaded the liver by penetrating through the diaphragm. After confirming the presence of tuberculous lesions in the chest wall and liver, both patients received preoperative anti-tuberculosis (TB) medications for two weeks; after which, the lesions were surgically removed. Following surgery, both patients fully recovered and were asymptomatic, but continued to receive routine postoperative care involving anti-TB medications. Neither patient showed recurrence of TB during a 15-month follow-up period.

The clonal evolution and therapeutic approaches of lung cancer.

According to the World Cancer Research Foundation, the newly diagnosed annual lung cancer cases all over the world are alarmingly high at 12.5 %. It also shows the highest mortality rate among all the cancer types. Nearly 225,000 new lung cancer patients are reported annually in the USA. The lung cancer cells also have very fast growth rates. As a result of this rapid proliferation rate, the lung cancer cells are sensitive to the available therapeutics like the radiation, surgical, or chemo therapy. Notwithstanding all the advances in the field of tumor biology, the mortality rate with lung cancer has remained significantly high. Precise and early diagnosis of the disease can be an important step in the proper and successful setting up of the treatment modalities. There are no comprehensive reviews available that discusses all the basic and updated aspects of lung cancer. This review focuses on the basic aspects of lung cancer like the etiology, risk factors, and clonal evolution. Exposure to smoking comes up as a single major environmental cause of the disease. The classification of lung cancer has also been discussed in detail based on immunohistochemistry. The existing therapeutic approaches as well as the upcoming modern day interventions have been discussed with their pros and cons. Recent techniques like molecular profiling can prove to be highly beneficial if properly standardized. With such advancements in therapy in conjunction with the updated diagnostics, there is a real hope in the treatment of lung cancer.

Differential diagnosis of solitary pulmonary nodules using 99mTc-3P4-RGD2 scintigraphy.

PURPOSE: Targeting of integrin α(ν)ß(3) with molecular imaging agents offers great potential in early detection and monitoring of tumour angiogenesis. Recently, an RGD (Arg-Gly-Asp) tracer, (99m)Tc-3P(4)-RGD(2), with high affinity to integrin α(ν)ß(3) and in vivo tumour uptake was developed. In this study, we evaluate the feasibility of this novel radiotracer in the noninvasive differentiation of solitary pulmonary nodules (SPNs). METHODS: Twenty-one patients with SPNs on CT were studied scintigraphically after administration of (99m)Tc-3P(4)-RGD(2) with a dose of 939 ± 118 MBq. Image interpretation using a 5-point scale was performed by one thoracic radiologist for CT and three nuclear medicine radiologists for single photon emission computed tomography (SPECT). Scintigraphic images were also analysed semiquantitatively by calculating tumour to normal tissue ratio (T/N). The "gold standard" was based on the histopathological diagnosis of the surgical samples from all recruited patients. A fraction of the samples were analysed immunohistochemically for integrin α(v)ß(3) expression. RESULTS: Among the 21 SPNs, 15 (71%) were diagnosed as malignant and 6 (29%) were benign. The mean size for SPNs was 2.2 ± 0.6 cm. The sensitivity and specificity for CT interpretation, SPECT visual and semiquantitative analysis were 80/67%, 100/67% and 100/67%, respectively. All SPNs classified as indeterminate by CT were correctly diagnosed by (99m)Tc-3P(4)-RGD(2) scintigraphy. The empirical receiver-operating characteristic (ROC) areas were 0.811 [95% confidence interval (CI) 58-95%] for CT, 0.833 (95% CI 61-96%) for SPECT and 0.844 (95% CI 62-96%) for T/N ratios, respectively. Immunohistochemistry confirmed α(ν)ß(3) expression in malignant and benign nodules with uptake in (99m)Tc-3P(4)-RGD(2) scintigraphy. CONCLUSION: In this first-in-human study, we demonstrated the feasibility of using (99m)Tc-3P(4)-RGD(2) scintigraphy in differentiating SPNs. This procedure appears to be highly sensitive in detection of malignant SPNs. SPECT visual analysis seems to be sufficient for characterization of SPNs.

[Effect of tissue factor in extravascular migration of fibrosarcoma cells].

OBJECTIVE: To evaluate the effect of tissue factor (TF) in extravascular migration of fibrosarcoma cells and hematogenous metastasis. METHODS: The expression of tissue factor in fibrosarcoma HT1080 cells was analyzed by flow cytometry. The extravascular migration of fibrosarcoma cells was observed in a constructed monolayer vascular endothelial cells and extra-cellular matrix model. RESULT: Tissue factor was highly expressed in HT1080 cells. HT1080 migrated and passed through the monolayer vascular endothelial cells to the collagen gel in a time-dependent manner. Anti-TF antibody inhibited extravascular migration of fibrosarcoma cells and the inhibition was concentration-dependent (P<0.05). CONCLUSION: Tissue factor may enhance hematogenous metastasis through extravascular migration of fibrosarcoma cells.

[Mechanism of endothelial Rho/Rho kinase in extravascular migration of fibrosarcoma cell].

OBJECTIVE: To study the mechanism of endothelial Rho/Rho kinase in extravascular migration of fibrosarcoma cell. METHODS: We used an in vitro model of fibrosarcoma cell transmigration across a monolayer of human umbilical vein endothelial cell (HUVEC) cultured on collagen gel to observe extravascular migration of fibrosarcoma cells, and then calculated the electrical resistance of HUVEC monolayer and endothelial myosin light chain (MLC) phosphorylation in extravascular migration of fibrosarcoma cells. RESULTS: Fibrosarcoma cells migrated through endothelial cells into collagen gel. The electrical resistance of a HUVEC monolayer reduced and endothelial MLC phosphorylation enhanced in the extravascular migration of fibrosarcoma cells. Endothelial Rho inhibitor (C3 transferase) and Rho kinase inhibitor (Y-27632) inhibited the extravascular migration of fibrosarcoma cells and inhibited the reduction of electrical resistance of a HUVEC monolayer and the enhancement of endothelial MLC phosphorylation in extravascular migration of fibrosarcoma cells. CONCLUSION: Endothelial Rho/Rho kinase may regulate fibrosarcoma cell transendothelial migration through MLC phosphorylation.

[Functional regulation of endothelial Myosin light chain kinase in extravascular migration of fibrosarcoma cells].

OBJECTIVE: To evaluate the functional regulation of endothelial Myosin light chain kinase (MLCK) in extravascular migration of fibrosarcoma HT1080 cells. METHODS: An in vitro model of fibrosarcoma cell transmigration across a monolayer of HUVEC cultured on collagen gel was applied to observe extravascular migration of HT1080 cells,and were the electrical resistance of HUVEC monolayer and endothelial MLC phosphorylation in extravascular migration of HT1080 cells. RESULT: HT1080 cells migrated through endothelial cells into collagen gel, the electrical resistance of a HUVEC monolayer was reduced and endothelial MLC phosphorylation was enhanced in extravascular migration of fibrosarcoma cells. Endothelial MLCK inhibitor (ML-7) blocked extravascular migration of HT1080 cells and inhibited reduction of electrical resistance of a HUVEC monolayer and enhancement of endothelial MLC phosphorylation in extravascular migration of HT1080 cells in a dose-dependent manner. CONCLUSION: Endothelial MLCK regulates fibrosarcoma cell transendothelial migration through MLC phosphorylation, leading to cytoskeletal reorganization and endothelial cell constriction, then fibrosarcoma cells migrate into extravascular tissue through the gaps between endothelial cells.

Esophagectomy and cervical side-to-side stapled esophagogastric anastomosis.

OBJECTIVE: To determine the clinical effect and the prospect of cervical side-to-side stapled esophagogastric anastomosis. METHODS: Eighteen cases of upper and middle thoracic esophageal carcinoma were treated with esophagectomy and cervical side-to-side stapled esophagogastric anastomosis. The clinical data were collected and retrospectively analyzed. The average age of patients was 60.7 years and the ratio of male to female was 17:1. The tumor included 4 upper part and 14 middle thoracic parts. The length of tumors was from 1 cm to 7 cm, with an average of 3.2 cm. RESULTS: The post-operative TNM staging(AJCC) included 4 Stage IIa,9 Stage IIb,and 5 Stage III. The operative incisions included 8 nontransthoracic cervical and abdominal double incisions, 9 right cervico-thoraco-abdominal triple incisions, and 1 left cervico-thoracic incision. One (5.56%) patient complicated with anastomotic leakage and was cured in 2 weeks by cervical drainage and absolute diet. All the 18 patients were followed up for 1 to 5 years,and no anastomotic stricture was found. Reflux esophagitis was found in 2 and the incidence rate was 11.11%. CONCLUSION: Cervical side-to-side esophagogastric anastomosis is a safe procedure with larger resection of margins and fewer complications. It is worth replicating.

Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase.

Adriamycin (ADR) is a commonly used chemotherapeutic agent that is believed to exert its effects through the generation of oxygen free radicals. We hypothesized that administration of a single dose of ADR results in endothelial nitric oxide synthase (eNOS)-dependent generation of superoxide (O2*-) and acute endothelial dysfunction. A single dose of ADR (10 mg/kg i.v.) administered to rabbits resulted in rapid attenuation of agonist-dependent responses to acetylcholine and calcium ionophore (A23187). In vitro exposure of ring segments to ADR for < 30 min resulted in O2*- generation measured by electron spin resonance (ESR) with the spin trap segments 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) that was abolished by endothelial denudation and incubation with diphenyliodonium (DPI) (10 microM) but not L-NMMA (10 microM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 +/- 1.0 to 2.5 +/- 1.1% (p = 0.0004, time to end of infusion 27 +/- 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 +/- 3.1 and 14.33 +/- 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 +/- 6 micromol/l pre-ADR to 33 +/- 6 micromol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Willebrand factor (vWF) activity remained unchanged after ADR infusion (36 +/- 13 to 52 +/- 22% ng/ml versus 3.25 +/- 0.98 to 3.01 +/- 0.91%, respectively, p = NS for pre versus post for both). Doppler indices of diastolic function (IVRT, DT and E/A ratios) were not altered in response to ADR. In conclusion, ADR administration results in rapid depletion of systemic NO* levels and attenuation of agonist-dependent responses in rabbits and flow-mediated dilation in the brachial artery of humans. ESR measurements in rabbit ring suggest an endothelial origin for radical production via flavin-containing oxido-reductases such as eNOS or NADPH cytochrome P450 reductase. These findings may have implications for cardiovascular complications noted with ADR.

Effect of electrolyzed oxidizing water and hydrocolloid occlusive dressings on excised burn-wounds in rats.

OBJECTIVE: To study the efficacy of electrolyzed oxidizing water (EOW) and hydrocolloid occlusive dressings in the acceleration of epithelialization in excised burn-wounds in rats. METHODS: Each of the anesthetized Sprague-Dawley rats (n=28) was subjected to a third-degree burn that covered approximately 10% of the total body surface area. Rats were assigned into four groups: Group I (no irrigation), Group II (irrigation with physiologic saline), Group III (irrigation with EOW) and Group IV (hydrocolloid occlusive dressing after EOW irrigation). Wounds were observed macroscopically until complete epithelialization was present, then the epithelialized wounds were examined microscopically. RESULTS: Healing of the burn wounds was the fastest in Group IV treated with hydrocolloid occlusive dressing together with EOW. Although extensive regenerative epidermis was seen in each Group, the proliferations of lymphocytes and macrophages associated with dense collagen deposition were more extensive in Group II, III and IV than in Group I. These findings were particularly evident in Group III and IV. CONCLUSIONS: Wound Healing may be accelerated by applying a hydrocolloid occlusive dressing on burn surfaces after they are cleaned with EOW.

Incomplete retention after direct myocardial injection.

Direct intramyocardial injection may permit local delivery of protein and gene therapy agents for myocardial and coronary artery disease. Little is known about the immediate fate of materials administered via percutaneous endomyocardial catheters or via surgical epicardial injection. In this study, we use a novel method to evaluate the acute retention of agents injected directly into the myocardium, compare epicardial with the percutaneous endocardial and postmortem delivery, and evaluate the influence of injectate volume on myocardial retention. Fifteen 40-50 kg pigs underwent overlapping myocardial injections using a percutaneous endomyocardial catheter, an epicardial needle via an open chest, and epicardial needle postmortem. Multiple distinct 15 micro neutron-activated microsphere species were used as tracers. Two or three myocardial walls were injected in each animal using 3.5 mm, 27-28 gauge needles at varying injectate volumes. Animals were sacrificed immediately. Myocardial walls were divided and multiple microsphere species were quantified. In an additional study, nine 70 kg pigs underwent percutaneous endomyocardial injections with replication-deficient adenovirus encoding for the production of lac-Z. The injectate volume was varied, while the viral particle number remained constant. The animals were sacrificed 5 days after the percutaneous injections; the heart, liver, and spleen were collected for beta-galactosidase activity. Endomyocardial injection was associated with 43% +/- 15% microsphere retention, compared with 15% +/- 21% (P < 0.01) retention of open chest epicardial injection and 89% +/- 60% (P < 0.01) for postmortem injection. Reducing the injectate volume from 100 to 10 microL improved microsphere retention (P = 0.01). There was a trend toward improved viral transfection associated with smaller injection volumes. Despite direct intramyocardial administration, a significant fraction of injectate is not retained locally. Catheter-based needle endomyocardial injection is associated with equivalent or superior injectate retention compared with open chest epicardial injection. Proportionately, more injectate may be retained at lower volumes. Loss may involve a combination of channel leakage, venous, and lymphatic return.

Ultrasound-mediated transfection of canine myocardium by intravenous administration of cationic microbubble-linked plasmid DNA.

We tested the hypothesis that targeted disruption of cationic microbubble-linked plasmid DNA, using diagnostic ultrasound, may aid transfection of large animal myocardium. Plasmid DNA encoding for CAT (pCAT, chloramphenicol acetyltransferase) was bound to a novel cationic microbubble containing MRX-225 for intravenous administration, and 16 dogs in 4 groups variously received this conjugate or plasmid only, or were exposed to ultrasound. Histochemical staining and enzyme-linked immunosorbent assay analysis showed CAT activity in the myocardium of only those animals that received microbubble-linked DNA and were exposed to ultrasound. Thus, disruption of cationic-linked, low-dose plasmid systems by diagnostic ultrasound may facilitate transfection of large animal hearts.