MLH1 Inhibits Metastatic Potential of Pancreatic Ductal Adenocarcinoma via Downregulation of GPRC5C.

DNA mismatch repair gene MutL homolog-1 (MLH1) has divergent effects in many cancers; however, its impact on the metastasis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, MLH1 stably overexpressed (OE) and knockdowned (KD) sublines were established. Wound healing and transwell assays were used to evaluate cell migration/invasion. In vivo metastasis was investigated in orthotopic implantation models (severe combined immunodeficiency mice). RT-qPCR and western blotting were adopted to show gene/protein expression. MLH1 downstream genes were screened by transcriptome sequencing. Tissue microarray-based immunohistochemistry was applied to determine protein expression in human specimens. In successfully generated sublines, OE cells presented weaker migration/invasion abilities, compared with controls, whereas in KD cells, these abilities were significantly stronger. The metastasis-inhibitory effect of MLH1 was also observed in mice. Mechanistically, G protein-coupled receptor, family C, group 5, member C (GPRC5C) was a key downstream gene of MLH1 in PDAC cells. Subsequently, transient GPRC5C silencing effectively inhibited cell migration/invasion and remarkably reversed the proinvasive effect of MLH1 knockdown in KD cells. In animal models and human PDAC tissues, tumoral GPRC5C expression, negatively associated with MLH1 expressions, was positively correlated with histologic grade, vessel invasion, and poor cancer-specific survival. In conclusion, MLH1 inhibits the metastatic potential of PDAC via downregulation of GPRC5C.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

Outcomes of surgical treatment for active infective endocarditis under COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been and will continue to be a challenge to the healthcare system worldwide. In this context, we aimed to discuss the impact of the COVID-19 pandemic on the diagnosis, timing, and prognosis of surgical treatment for active infective endocarditis (IE) during the pandemic and share our coping strategy. METHODS: A total of 39 patients were admitted for active IE in the year 2020. The number of the same period last year was 50. Medical information of these two groups was extracted from our surgical database. Data were compared between the two groups and differences with or without statistical significance were discussed. RESULTS: In the pandemic year, we admitted fewer transferred patients (64.1% vs. 80%, p = .094). Timespan for diagnosis were prolonged (60 vs. 34.5 days, p = .081). More patients were admitted in emergency (41% vs. 20%, p = .030) More patients had heart failure (74.4% vs. 40%, p = .001), sepsis (69.2% vs. 42.0%, p = .018), or cardiogenic shock (25.6% vs. 8.0%, p = .038). Overall surgical risk (EuroSCORE II) was higher (4.15% vs. 3.24%, p = .019) and more commando surgery was performed (7.7% vs. 2.0%, p = .441). However, we did not see more postoperative complications, and early mortality was not worse either (0 vs. 4%, p = .502). CONCLUSIONS: The negative impact of the COVID-19 pandemic on the clinical practice of surgical treatment for active IE was multifaceted. However, with the preservation of the effectiveness of multidisciplinary IE surgical team, the early outcomes were comparable with those in the normal years.

Repair versus replacement for active endocarditis of the mitral valve: 9 years of experience.

BACKGROUND AND AIM: To determine the factors contributing to successful mitral valve repair (MVP) and to discuss the effect of complex techniques on the durability of MVP for active infective endocarditis (IE) affecting the mitral valve. METHODS: One hundred and eighty-seven patients were enrolled; 39.6% underwent mitral valve replacement (MVR) and 60.4% underwent MVP. We used logistic regression to identify influencing factors of the choice of surgical technique. The results were compared between groups and subgroups after propensity score matching (PSM). RESULTS: Risk factors for MVR included poor valve quality (odds ratio [OR] 23.3, p = .001), a large defect after debridement (OR 16.4, p < .001), and heavy valve infection (OR 3.7, p = .027). After PSM, we did not find a significant difference in the frequency of major postoperative complications or the in-hospital or postdischarge death rate. The reintervention rate for MVP was significantly higher than that for MVR (p = .047). Subgroup analysis found a significant relationship between the use of a complex repair technique and the need for reoperation (p = .020). CONCLUSIONS: The choice of valve repair or replacement for patients with active IE affecting the mitral valve was influenced by the intraoperative characteristics of the infected valve rather than the severity of systemic infection or overall health status. The choice of surgical treatment strategy had no effect on major postoperative complications, in-hospital mortality, or medium-term survival. However, the medium-term durability of MVP was poorer than that of MVR. The use of the patch technique for free margins or extensive leaflet defects was associated with a need for reintervention.

Reversible Myocardial Calcification Following Acute Heart Failure and Kidney Injury Caused by Valsalva Sinus Rupture.

A 47-year-old previously healthy man was referred to a local hospital with chest tightness, oliguria, and lower extremity edema for seven days. An initial investigation revealed acute heart failure and kidney injury. The patient was intensively treated with cardiac and renal replacement therapy, and cardiorenal function improved one week later. Two months later, echocardiography was performed because chest tightness and edema had not resolved. Echocardiography showed Valsalva sinus rupture, and the patient was transferred to our center. Myocardial calcification was observed in the left ventricular wall on computed tomography after admission. The patient underwent cardiac surgery and recovered smoothly. At the three-year follow up, the patient was asymptomatic with normal renal function and serum electrolytes. Imaging revealed a significant reduction in diffuse calcification of the left ventricular wall. This case indicates that this rare form of reversible myocardial calcification may be associated with acute heart and renal failure caused by Valsalva sinus rupture. The results of this case will guide clinicians about further management and timely referral of such patients to appropriate specialties.

Comparison of Sternal Fixation Strategies After Open-Heart Surgery Via a Median Sternal Incision.

OBJECTIVES: To explore the personalized treatment strategy of sternal fixation and closure of sternal median incision in open cardiac surgery. METHODS: A total of 293 patients who underwent open-heart surgery with a median sternal incision at Peking Union Medical College Hospital from January 2019 to March 2021 were divided into two groups, according to the timing and type of treatment. The first 169 patients received single-wire fixation and closure (control group), while the subsequent 124 patients received double-wire fixation and closure (study group). The patients were followed up for three months to observe the duration of pain, sternal instability, and occurrence of chest wound infection. RESULTS: The average age was 53±30 years in the control group and 55±34 years in the study group (P = 0.594). There were no significant differences in baseline data between the two groups (P > 0.05). Compared with the control group, the study group had a shorter duration of pain (P < 0.05), smaller drainage volume within three days postoperatively (650 ml vs. 770 ml, P < 0.05), lower incidence of superficial sternal wound infection (2.4% vs. 8.9%, P = 0.042), and lower incidence of sternal instability (1.6% vs. 8.3%, P = 0.026). Deep sternal wound infection occurred in two patients in the control group and none in the study group; however, this difference was not significant. No surgery-related deaths occurred. CONCLUSIONS: Selecting the appropriate sternal fixation and closure method, according to the characteristics of patients, can reduce the incidence of sternal incision complications. We proposed a personalized selection strategy for sternal fixation and closure, which requires verification in clinical studies.

Tracer-Based Cancer Metabolomic Analysis.

Metabolic rewiring/reprogramming is an essential hallmark of cancer. Alteration of metabolic phenotypes is occurred in cancer cells in response to a harsh condition to support cancer cell proliferation, survival, and metastasis. Stable isotope can be used as a tracer to investigate the redistribution of the carbons labeled in glucose in order to elucidate the detailed mechanisms of cellular rewiring and reprogramming in tumor microenvironment. Stable isotope-resolved metabolomics (SIRM) is an analytical method inferring metabolic networking by using advanced nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to analyze the fate of a single atom from a stable isotope-enriched precursor to a product metabolite. This methodology has been demonstrated for a wide range of biological applications, including cancer metabolomic analysis. The basic principle and platforms of SIRM and its implication for cancer metabolism research will be addressed in this chapter.

Regulatory T-cells promote pulmonary repair by modulating T helper cell immune responses in lipopolysaccharide-induced acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) induces a strong local infiltration of regulatory T-cells (Tregs) in the lungs. However, at present, there remains a lack of adequate evidence showing the direct effect of Tregs on pulmonary repair and the related mechanisms of ARDS. Therefore, in this project, we studied the impact of Tregs on lipopolysaccharide (LPS)-induced ARDS and pulmonary inflammation. Surprisingly, we found that depletion of Tregs by injection of PC61 anti-CD25 antibody not only interfered with the inflammation resolution, such as inhibited total cell infiltration into the alveolar space, downregulated neutrophils, upregulated macrophages, but also impaired pulmonary epithelium and endothelial cell proliferation. Consistent with the attenuation of pulmonary repair, we found that the Th1 and Th17 immune responses were also impaired in Treg-depleted mice, suggesting that the presence of Tregs is vital for tissue repair, as Tregs modulate and promote the Th immune response in LPS-induced pulmonary inflammation.

MicroRNA Detection with Turnover Amplification via Hybridization-Mediated Staudinger Reduction for Pancreatic Cancer Diagnosis.

The occurrence of and development in the early pathological stage of pancreatic cancer has proved to be associated with microRNAs. However, it remains a great challenge to directly monitor low-expression, and downregulation of, microRNA among living cells, tissues, and serum samples. In this work, Staudinger reduction is first applied in intracellular microRNA detection, establishing a set of smart hybridization-mediated Staudinger reduction probes (HMSR-probe) which contain designed oligonucleotide sequences. Meanwhile, 40 serum samples (healthy people (6), patients with pancreatitis (22), and pancreatic cancer patients (12)) are tested for exploring the potential clinical application. Of note, the molecules bound to nucleic acid confine the reactive site to close proximity in a compact space, and nonconnected product from Staudinger reaction facilitates turnover amplification to an ameliorative detection limit (1.3 × 10-15 M). Moreover, compared with qRT-PCR, a low false positive signal and an excellent specificity makes the probe more suitable and convenient for pancreatic cancer diagnosis in blood samples. For practical applications, HMSR-probe enable accurate differentiation in cell and tissue samples under both 488 and 785 nm and have good coherence to known research. As a proof of concept, the reliable results in distinguishing pancreatic cancer patients from different morbid stages might supply a feasible method for endogenous microRNA detection in fundamental research and clinical diagnostics.

Remote Ischemic Preconditioning has a Cardioprotective Effect in Children in the Early Postoperative Phase: A Meta-Analysis of Randomized Controlled Trials.

In this updated meta-analysis, we assessed the cardioprotective effect of remote ischemic preconditioning (RIPC) in pediatric patients undergoing congenital heart surgery. A total of 9 randomized controlled trials (RCTs) involving 793 pediatric patients under 18 years old were identified. RIPC obviously reduced the release of troponin I at 6 h after surgery [standard mean difference (SMD) -0.59, 95% confidence interval (CI) -1.14 to -0.04; p = 0.03], mitigated the inotropic scores within 4-6 h (SMD -0.43, 95% CI -0.72 to -0.14; p = 0.004) and within 12 h (SMD -0.26, 95% CI -0.50 to -0.02; p = 0.03) and shortened the ventilator support time (SMD -0.28, 95% CI -0.49 to -0.07; p = 0.01) as well as the duration of intensive care unit (ICU) stay (SMD -0.21, 95% CI -0.35 to -0.06; p = 0.004). Our meta-analysis determined that RIPC had cardioprotective effects in the early postoperative phase. Additional RCTs focused on the cardiac benefits from RIPC in pediatric patients are warranted.

MicroRNAs as effective surrogate biomarkers for early diagnosis of oral cancer.

BACKGROUND: Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns. OBJECTIVE: Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer. METHODS: A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer. RESULTS: In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, Notch signaling, and TGF-ß/SMAD signaling pathway. CONCLUSIONS: A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility. CLINICAL RELEVANCE: These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.

Use of freeze-dried bone allografts in osteoporotic patients undergoing median sternotomy.

Osteoporosis is a major risk factor for deep sternal wound infection, which is a rare but serious complication after median sternotomy. We investigated the incidence of deep sternal wound infection and the protective effect of bone allografts in osteoporotic patients after sternal approximation. Data were collected retrospectively from consecutive osteoporotic patients who underwent cardiac surgery via median sternotomy. Sternal approximation in the historical control group was performed with conventional steel wire sutures. Subsequent patients underwent conventional wire suturing plus bone allografting to reinforce the sternum. Perioperative management was standardized between groups. Demographics, risk factors, and postoperative outcomes were analyzed. Between January 2010 and March 2017, 284 patients underwent sternal approximation after sternotomy at our hospital. Sternal closure was completed with conventional wire sutures in the first 148 patients (Group A) and with conventional wire sutures plus bone allografting in the subsequent 136 patients (Group B). Baseline characteristics were comparable, with no significant differences between groups. Bone allografting was associated with less postoperative drainage and shorter duration of chest pain. The incidence of deep sternal wound infection was significantly lower in Group B than Group A (0.7 vs. 4.7%, P = 0.042), as was the incidence of sternal instability (0.7 vs. 7.4%, P = 0.043). Bone allografting was a reliable adjuvant method for sternal closure, associated with reduced risk of deep sternal wound infection among osteoporotic patients. Its benefits should be confirmed in larger studies.

Metabolic Regulation in Mitochondria and Drug Resistance.

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.

Surgical Treatment Strategies of Intravenous Leiomyomatosis withRight Cardiac Cavities Extension.

Objective To investigate the diagnosis and surgical treatment strategies of intravenous leiomyomatosis(IVL)extending through inferior vena cava into the right cardiac cavities. Methods Thirty patients of IVL extending through inferior vena cava into the right cardiac cavities were treated in Peking Union Medical College Hospital from November 2002 to January 2015.The following variables were studied: age,cardiopulmonary bypass time,deep hypothermic circulatory arrest time,origins of IVL,blood loss,duration of post-operative hospital stay,hospitalization expenses,edema of lower extremity,blood transfusion,postoperative complication,residual IVL,and re-grow or recurrence. Results Thirteen of 30 patients reported double lower limb edema. The cardiopulmonary bypass was applied in 27 cases,and the average duration of cardiopulmonary bypass was(106.9±53.7)min. Then,21 patients were treated with the deep hypothermic circulatory arrest,and the mean time was(28.2±11.6) min. The tumors originated from the genital veins in 9 cases,the iliac vein in 13 cases,and both veins in 8 cases. The average intra-operative blood loss volume was (2060.5±2012.3)ml,and 21 patients received blood transfusion. The average hospitalization time was(18.9±8.3)days and the average hospitalization expenses was (80 840.4±28 264.2)RMB yuan. While 14 patients had postoperative complications,there was no serious postoperative complication or death.All patients have shown a favorable outcome.Conclusions Tumor embolus extending through inferior vena cava into the right cardiac cavities should be suspected in patients with multiple hysteromyoma. Successful therapy for IVL with right cardiac cavities extension is dependent on reasonable surgical treatment strategies. Surgical removal of the ovaries is vital to avoid IVL re-grow or recurrence.

[Endoscopic Saphenous Vein Harvesting versus Open Vein Harvesting Techniques].

OBJECTIVE: To investigate whether endoscopic saphenous vein harvesting (EVH )reduces leg wound morbidity and improves rehabilitation of lower extremity as compared to open vein harvesting (OVH) in patients with coronary artery disease. METHODS: The clinical data of 333 patients who underwent isolated coronary artery bypass graft surgery (CABG) between January 2007 and December 2011 were retrospectively analyzed.These patients were divided into EVH group (n=210) and OVH group (n=123). Parameters including age,sex,with/without diabetes mellitus,leg wound complications rate,postoperative hospital stay,hospitalization expense,and vein graft patency were analyzed. RESULTS: The age,sex,with/without diabetes mellitus were not significantly different between two groups (P>0.05). However,the incidences of leg wound complications, poor wound healing, wound infections, wound pain,wound numbness, and edema of lower extremity were significantly lower in the EVH group than the OVH group (P<0.05). The ecchymoma and deep vein thrombosis incidences were not significantly different between these two groups (P>0.05). The postoperative hospital stay showed no significant difference (P>0.05), while the hospitalization expense was significantly higher in the EVH group than in the OVH group (P<0.05). There was no statistical difference of vein graft patency (P>0.05). CONCLUSION: The EVH system is a safe and effective alternative to OVH because it can markedly reduce postoperative leg wound morbidity and the EVH vein graft has good patency.

Tumor microenvironment crosstalk between tumors and the nervous system in pancreatic cancer: Molecular mechanisms and clinical perspectives.

Pancreatic ductal adenocarcinoma (PDAC) exhibits the highest incidence of perineural invasion among all solid tumors. The intricate interplay between tumors and the nervous system plays an important role in PDAC tumorigenesis, progression, recurrence, and metastasis. Various clinical symptoms of PDAC, including anorexia and cancer pain, have been linked to aberrant neural activity, while the presence of perineural invasion is a significant prognostic indicator. The use of conventional neuroactive drugs and neurosurgical interventions for PDAC patients is on the rise. An in-depth exploration of tumor-nervous system crosstalk has revealed novel therapeutic strategies for mitigating PDAC progression and effectively relieving symptoms. In this comprehensive review, we elucidate the regulatory functions of tumor-nervous system crosstalk, provide a succinct overview of the relationship between tumor-nervous system dialogue and clinical symptomatology, and deliberate the current research progress and forthcoming avenues of neural therapy for PDAC.

Quadruple valve replacement for patient with infective endocarditis 16 years after Fallot's Tetralogy Repair procedure: A case report.

A 33-year-old man, who had previously undergone repair for Tetralogy of Fallot, presented with extensive infective endocarditis. Following thorough preoperative preparation and evaluation, we performed a simultaneous quadruple valve replacement alongside the repatching of the remaining defect. We posit that this comprehensive one-stage surgical intervention not only enhanced the patient's quality of life but also reduced the necessity for future reoperations. Our approach offers valuable insights for managing adult patients with repaired congenital heart diseases and multiple valve pathologies.

Obg-like ATPase 1 exacerbated gemcitabine drug resistance of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.

Diagnosis, Genetics, and Management of 24 Patients With Cardiac Paragangliomas: Experience From a Single Center.

Context: Paragangliomas located within the pericardium represent a rare yet challenging clinical situation. Objective: The current analysis aimed to describe the clinical characteristics of cardiac paragangliomas, with emphasis on the diagnostic approach, genetic background, and multidisciplinary management. Methods: Twenty-four patients diagnosed with cardiac paraganglioma (PGL) in Peking Union Medical College Hospital, Beijing, China, between 2003 and 2021 were identified. Clinical data was collected from medical record. Genetic screening and succinate dehydrogenase subunit B immunohistochemistry were performed in 22 patients. Results: The median age at diagnosis was 38 years (range 11-51 years), 8 patients (33%) were females, and 4 (17%) had familial history. Hypertension and/or symptoms related to catecholamine secretion were present in 22 (92%) patients. Excess levels of catecholamines and/or metanephrines were detected in 22 (96%) of the 23 patients who have completed biochemical testing. Cardiac PGLs were localized with 131I-metaiodobenzylguanidine scintigraphy in 11/22 (50%), and 99mTc-hydrazinonicotinyl-tyr3-octreotide scintigraphy in 24/24 (100%) patients. Genetic testing identified germline SDHx mutations in 13/22 (59%) patients, while immunohistochemistry revealed succinate dehydrogenase (SDH) deficiency in tumors from 17/22 (77%) patients. All patients were managed by a multidisciplinary team through medical preparation, surgery, and follow-up. Twenty-three patients received surgical treatment and perioperative death occurred in 2 cases. Overall, 21 patients were alive at follow-up (median 7.0 years, range 0.6-18 years). Local recurrence or metastasis developed in 3 patients, all of whom had SDH-deficient tumors. Conclusion: Cardiac PGLs can be diagnosed based on clinical manifestations, biochemical tests, and appropriate imaging studies. Genetic screening, multidisciplinary approach, and long-term follow-up are crucial in the management of this disease.