Data_Sheet_1_Effectiveness and safety of inspiratory muscle training in patients with pulmonary hypertension: A systematic review and meta-analysis.docx

BackgroundInspiratory muscle training (IMT) is a simple and well-tolerated physical therapy that increases respiratory muscle strength and relieving the degree of dyspnea and fatigue. Therefore, it may be used as a transitional modality before exercise training or as a specific physical therapy intervention for those who are diagnosed with respiratory muscle weakness. However, the current evidence on IMT in pulmonary hypertension (PH) patients is inconclusive. The purpose of this systematic review and meta-analysis was to summarize the current role of IMT in this group of patients.MethodsPubMed, EMBASE, and Cochrane databases were searched through May 2022. Trials examining the feasibility and effectiveness of IMT in PH patients. Outcome measures included adverse events, training adherence and compliance, maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC%), forced expiratory volume in 1 s (FEV1%), FEV1/FVC%, 6 min walk distance (6MWD), Peak VO2, dyspnea, and fatigue perception after the IMT training program. Only randomized controlled trials were included. The Cochrane Risk of Bias tool for controlled trials was adopted to assess study quality. Statistical heterogeneity was evaluated with the chi-square test and I2 statistic. Mean differences and 95% confidence intervals (CIs) were estimated.ResultsWe ultimately identified four studies that met the criteria. These studies comprised 80 patients with 16 males and 64 females. The mean age was 53.25. The main types of PH were group I (pulmonary arterial hypertension, 95%) and group IV (chronic thromboembolic PH, 5%). No severe adverse events were reported in the included studies. IMT had a significant effect on improving MIP (18.89 cmH2O; 95% CI: 9.43–28.35, P 2O; 95% CI: 2.39–13.73; P = 0.005), increase in the 6MWD (30.16 m; 95% CI: 1.53–58.79; P = 0.04). No significant improvement was found in pulmonary function (P > 0.05), and uncertain effect on the quality of life (QoL) score.ConclusionBased on currently limited evidence, IMT is an effective physical therapy for increasing respiratory muscle function and exercise capacity, but still a lack of evidence on dyspnea and fatigue levels, pulmonary function, and QoL in PH patients. There are reasons to believe that IMT is a promising intervention in PH patients, enriching rehabilitation options and serving as a bridge before formal exercise training. It is expected that IMT will play an important role in the future clinical pathway of physical therapy for this group of patients.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/logout.php], identifier [CRD42022335972].</p

Data_Sheet_1_Physiological ischemic training improves cardiac function through the attenuation of cardiomyocyte apoptosis and the activation of the vagus nerve in chronic heart failure.docx

PurposeThis study investigated the functional outcomes of patients with chronic heart failure (CHF) after physiological ischemic training (PIT), identified the optimal PIT protocol, evaluated its cardioprotective effects and explored the underlying neural mechanisms.MethodsPatients with CHF were randomly divided into experimental group (n = 25, PIT intervention + regular treatment) and control group (n = 25, regular treatment). The outcomes included the left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP) and cardiopulmonary parameters. LVEF and cardiac biomarkers in CHF rats after various PIT treatments (different in intensity, frequency, and course of treatment) were measured to identify the optimal PIT protocol. The effect of PIT on cardiomyocyte programmed cell death was investigated by western blot, flow cytometry and fluorescent staining. The neural mechanism involved in PIT-induced cardioprotective effect was assessed by stimulation of the vagus nerve and muscarinic M2 receptor in CHF rats.ResultsLVEF and VO2max increased while BNP decreased in patients subjected to PIT. The optimal PIT protocol in CHF rats was composed of five cycles of 5 min ischemia followed by 5 min reperfusion on remote limbs for 8 weeks. LVEF and cardiac biomarker levels were significantly improved, and cardiomyocyte apoptosis was inhibited. However, these cardioprotective effects disappeared after subjecting CHF rats to vagotomy or muscarinic M2 receptor inhibition.ConclusionPIT improved functional outcomes in CHF patients. The optimal PIT protocol required appropriate intensity, reasonable frequency, and adequate treatment course. Under these conditions, improvement of cardiac function in CHF was confirmed through cardiomyocyte apoptosis reduction and vagus nerve activation.</p

Decreased TUSC3 Promotes Pancreatic Cancer Proliferation, Invasion and Metastasis - Fig 3

<p><b>TUSC3 is decreased in pancreatic cancer cell lines both at mRNA level (A) and protein level (B)</b>.</p

Decreased TUSC3 Promotes Pancreatic Cancer Proliferation, Invasion and Metastasis

<div><p>Pancreatic cancer is an aggressive disease with dismal prognosis. It is of paramount importance to understand the underlying etiological mechanisms and identify novel, consistent, and easy-to-apply prognostic factors for precision therapy. TUSC3 (tumor suppressor candidate 3) was identified as a potential tumor suppressor gene and previous study showed TUSC3 is decreased in pancreatic cancer at mRNA level, but its putative tumor suppressor function remains to be verified. In this study, TUSC3 expression was found to be suppressed both at mRNA and protein levels in cell line models as well as in clinical samples; decreased TUSC3 expression was associated with higher pathological TNM staging and poorer outcome. In three pairs of cell lines with different NF-κB activity, TUSC3 expression was found to be reversely correlated with NF-κB activity. TUSC3-silenced pancreatic cancer cell line exhibited enhanced potential of proliferation, migration and invasion. In an orthotopic implanted mice model, TUSC3 silenced cells exhibited more aggressive phenotype with more liver metastasis. In conclusion, the current study shows that decreased immunological TUSC3 staining is a factor prognostic of poor survival in pancreatic cancer patients and decreased TUSC3 promotes pancreatic cancer cell proliferation, invasion and metastasis. The reverse correlation between NF-κB activity and TUSC3 expression may suggest a novel regulation pattern for this molecule.</p></div

TUSC3 expression is associated with clinical pathological staging and Ki67 index.

<p>TUSC3 expression is associated with clinical pathological staging and Ki67 index.</p

Univariate and Multivariate Cox Proportional Hazard Analysis of Factors Affecting Recurrence-free and Overall Survival in Pancreatic Cancer.

<p>Univariate and Multivariate Cox Proportional Hazard Analysis of Factors Affecting Recurrence-free and Overall Survival in Pancreatic Cancer.</p

Decreased TUSC3 expression promotes tumor cell growth, migration and invasion.

<p>(A, B)TUSC3 is effectively knocked-down in Colo357 cell lines shown by (A) RT-PCR and (B) Western blot. (C, D) Proliferation is enhanced with TUSC3 knockdown, cell number counts are significantly different at 72 hours (Colo357 TUSC3 shRNA2 vs Colo357 Scramble p = 0.0086, Colo357 TUSC3 shRNA3 vs Colo357 Scramble p = 0.0011) (D). (E, F) Colony Formation is enhanced with TSUC3 knockdown (Colo357 TUSC3 shRNA2 vs Colo357 Scramble p<0.0001, Colo357 TUSC3 shRNA3 vs Colo357 Scramble p<0.0001). (G) Migration Test(Colo357 TUSC3 shRNA2 vs Colo357 Scramble p<0.0001, Colo357 TUSC3 shRNA3 vs Colo357 Scramble p<0.0001). (H, I) Invasion Test (Colo357 TUSC3 shRNA2 vs Colo357 Scramble p<0.0001, Colo357 TUSC3 shRNA3 vs Colo357 Scramble p<0.0001). (J) Wound healing test showed more rapid closure of the gap in TUSC3 silenced cells. All experiments were performed three times with representative figures shown as above.</p

TUSC3 is regulated by NF-κB activity shown by three pairs of pancreatic cancer cell lines.

<p>(A) AsPC-1 and AsPC-1 mu with depressed NF-κB activity. (B) MDA p28 and MDA p28 mu with depressed NF-κB activity. (C) Colo357 and the daughter L3.6pl cell line with enhanced NF-κB activity. For each figure, left graph represents RT-PCR result, right graph represents Western blot for TUSC3.</p

TUSC3 silenced pancreatic tumor cells exhibit more potential of liver metastasis in an orthotopic Balb/C nude mouse model.

<p>(A) Gross appearance of the resected liver specimens from mice injected with two groups of TUSC3 silenced PC (Colo357 shRNA2 and Colo357 shRNA3) and control (Colo357 Scramble). Large liver metastases are visible in group Colo357 shRNA2 and Colo357 shRNA3. (B) The liver metastases were weighted and compared using t-test.</p

TUSC3 is decreased in pancreatic cancer samples.

<p>(A) TUSC3 expression in non-neoplastic pancreatic tissues (acinar, duct and islets). (B) TUSC3 expression in pancreatic cancer cells. (C) Low TUSC3 expression in pancreatic cancer cells compared to islets. (D) Comparison of TUSC3 staining in primary PC and LN metastasis(paired t-test, p<0.001, n = 58). Original magnification×200.</p