Journal of Investigative Medicine

Immunotherapy is an extremely important breakthrough and an exciting new modality of treatment for a wide spectrum of cancers. It is focused around developing agents to stimulate or suppress the immune system, in a specific manner, to fight off a wide spectrum of diseases, particularly cancers. Traditional therapies available for the treatment of cancers include surgical intervention, chemotherapy, radiation therapy or a combination of these, which tend to be very non-specific. However, immunotherapy shows a stark difference from conventional therapy, in fact, that it has a high level of specificity for the tumor-specific antigens. The recent success of cancer immunotherapies in clinical trials is slowly revolutionizing the landscape for cancer therapy. The US Food and Drug Administration has approved numerous agents, after clinical trials showed promising results, for the treatment of multiple cancers. The role of immunotherapy in gastrointestinal cancers has also been very promising, particularly in patients with advanced metastatic disease or malignancies refractory to initial treatment. In this review of literature, we detail and discuss the immunotherapy agents approved for the treatment of GI cancers and glance at the future of immunotherapy for patients with these cancers.

Patients with type 2 diabetes have high levels of malondialdehyde (MDA), and clinical data suggest a reducing effect of rosiglitazone (RSG) on the level of MDA in these patients. However, the results of available studies on the level of MDA in RSG-treated patients are not univocal. This meta-analysis aimed to assess the impact of RSG on the level of MDA. We performed a comprehensive search of PubMed, the Institute for Scientific Information Web of Science, Embase, Scopus, and Cochrane Library for related controlled trials until July 2020. Eligible studies were selected based on the inclusion criteria. Extracted data from each study were combined using a random-effects model. Sensitivity and subgroup analyses were conducted to explore potential heterogeneity. Eight trials with 456 subjects met the inclusion criteria. The results significantly showed the reducing effect of RSG on circulating MDA level (−0.47 μmol/mL; 95% CI −0.93 to −0.01; p=0.04; I²=82.1%; p heterogeneity=0.00) in individuals with T2D. No publication bias was observed with Begg's rank correlation (p=0.71) and Egger's linear regression (p=0.52) tests. Subgroup analyses showed that an intervention dose of 8 mg/day in serum samples was found to have a reducing effect on the level of MDA (−0.56 μmol/mL; 95% CI −0.98 to −0.14; p=0.008; I²=11.4%; p heterogeneity=0.32). Random-effects meta-regression did not show any significant association between the level of MDA and potential confounders including RSG dose, treatment duration, and sex. In conclusion, we found a significant reduction in MDA concentration in subjects with T2D who received a dose of 8 mg of RSG daily.

China has experienced an outbreak of COVID-19 since December 2019. This study investigated the differences between the imported and local cases of COVID-19 in Nanyang, China. In this study, a total of 129 COVID-19 confirmed cases with a clear epidemiological history admitted to hospitals in Nanyang from January 24 to February 26, 2020 were enrolled. Patients who had a travel history to or a residence history in Wuhan or in the surrounding areas in Hubei Province within 14 days before the illness onset were assigned to the imported group (n=70), and the others were assigned to the local group (n=59). The differences in epidemiological characteristics, clinical features, laboratory and imaging results, and prognosis were compared between the 2 groups. The early diagnosed cases were mainly imported cases, and the later diagnosed ones were mainly local cases. The most common first symptom was fever; moderate fever was commonly seen in imported cases whereas low fever was commonly seen in local cases. Lymphocyte counts in the imported group were lower than those in the local group. The imported group showed more advanced and severe abnormalities in the CT scan whereas the local group showed milder pulmonary abnormalities. The proportion of severe and critically severe patients in the imported group was higher than that in the local group. In conclusion, the imported cases have more severe or critically severe patients with a higher mortality rate than the local cases.

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic leading to coronavirus disease 2019 (COVID-19) is straining hospitals. Judicious resource allocation is paramount but difficult due to the unpredictable disease course. Once hospitalized, discerning which patients may progress to critical disease would be valuable for resource planning. Medical records were reviewed for consecutive hospitalized patients with COVID-19 in a large healthcare system in Texas. The main outcome was progression to critical disease within 10 days from admission. Albumin trends from admission to 7 days were analyzed using mixed-effects models, and progression to critical disease was modeled by multivariable logistic regression of laboratory results. Risk models were evaluated in an independent group. Of 153 non-critical patients, 28 (18%) progressed to critical disease. The rate of decrease in mean baseline-corrected (Δ) albumin was −0.08 g/dL/day (95% CI −0.11 to −0.04; p<0.001) or four times faster, in those who progressed compared with those who did not progress. A model of Δ albumin combined with lymphocyte percentage predicting progression to critical disease was validated in 60 separate patients (sensitivity, 0.70; specificity, 0.74). ALLY (delta albumin and lymphocyte percentage) is a simple tool to identify patients with COVID-19 at higher risk of disease progression when: (1) a 0.9 g/dL or greater albumin drop from baseline within 5 days of admission or (2) baseline lymphocyte of ≤10% is observed. The ALLY tool identified >70% of hospitalized cases that progressed to critical COVID-19 disease. We recommend prospectively tracking albumin. This is a globally applicable tool for all healthcare systems.

The aim of this study is to evaluate the mesenteric artery stenosis (MAS) in routinely performed CT angiography (CTA) of patients with severe aortic stenosis (AS) planned for transcatheter aortic valve implantation (TAVI) before the procedure. Patients with AS (AS group) who routinely underwent CTA before the TAVI procedure due to severe AS and patients who had CTA for other indications (control group) were retrospectively and sequentially scanned. The demographic characteristics of the patients in both groups were similar. Calcification and stenosis in the mesenteric arteries were recorded according to the localization of celiac truncus, superior mesenteric artery (SMA) and inferior mesenteric artery (IMA). Class 0-3 classification was used for calcification score. Stenoses with a stenosis degree ≥50% were considered as significant. A total of 184 patients, 73 patients with severe AS and 111 control groups, were included in the study. SMA and IMA calcification scores of patients with AS were significantly higher than the control group (p=0.035 for SMA and p=0.020 for IMA). In addition, the rate of patients with significant MAS in at least 1 artery (45.2% vs 22.5%, p=0.001) and the rate of patients with significant stenosis in multiple arteries were also significantly higher in the AS group (8.2% vs 1.8%, p=0.037). According to the study results, patients with AS are at a higher risk for MAS. Chronic mesenteric ischemia should be kept in mind in patients with AS who have symptoms such as non-specific abdominal pain and weight loss.

To determine associations between severity of hypertension and risk of starting dialysis in the presence or absence of diabetes mellitus (DM). A nationwide database with claims data on 258 874 people with and without DM aged 19-72 years in Japan was used to elucidate the impact of severity of hypertension on starting dialysis. Initiation of dialysis was determined from claims using International Classification of Diseases-10 codes and medical procedures. Using multivariate Cox modeling, we investigated the severity of hypertension to predict the initiation of dialysis with and without DM. Hypertension was significantly associated with the initiation of dialysis regardless of DM. The incidence of starting dialysis in those with systolic blood pressure (SBP) ≤119 mm Hg and DM (DM+) was almost the same as in those with SBP ≥150 mm Hg and absence of DM (DM−). In comparison with SBP ≤119 mm Hg, SBP ≥150 mm Hg significantly increased the risk of the initiation of dialysis about 2.5 times regardless of DM+ or DM−. Compared with DM− and SBP ≤119 mm Hg, the HR for DM+ and SBP ≥150 mm Hg was 6.88 (95% CI 3.66 to 12.9). Although the risks of hypertension differed only slightly regardless of the presence or absence of DM, risks for starting dialysis with DM+ and SBP ≤119 mm Hg were equivalent to DM− and SBP ≥150 mm Hg, indicating more strict blood pressure interventions in DM+ are needed to avoid dialysis. Future studies are required to clarify the cut-off SBP level to avoid initiation of dialysis considering the risks of strict control of blood pressure.

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) reduce blood pressure (BP) in obese patients with hypertension (HTN). We compared the effect of RYGB and SG on BP in obese patients with HTN at a large-volume, private bariatric surgery center using a propensity score analysis. The measurement and management of BP were exclusively left to the patient's provider without any involvement of Tulane investigators. At month 1, RYGB and SG equally decreased: (1) mean body weight: 12.7 vs 13.2 kg (p=not significant (NS)) (2) systolic/diastolic BP: 8.5/5.3 vs 8.0/4.2 mm Hg (p=NS) and (3) average number of antihypertensive medications from 1.5 to 0.8 and from 1.6 to 0.6 per patient (p=NS). From month 1 to 12, BP remained unchanged after RYGB but tended to increase from month 6 to 12 after SG. Remission of HTN occurred in 52% and 44% of patients after RYGB and SG. In contrast to the full effect of RYGB and SG on BP at 1 month, body weight decreases steadily over 12 months after RYGB and SG. In conclusion, early after surgery, RYGB and SG equally reduce BP in obese patients with HTN. Thereafter, RYGB has a more sustained effect on BP than SG.

The previous studies have shown that plasma chitotriosidase (CHIT) levels increase in many diseases with inflammation. However, there are no reported studies investigating the relationship between CHIT and chronic heart failure (CHF) which is an inflammatory process. Therefore, we aimed to investigate the role of CHIT in diagnosis and severity of CHF in this study. 36 patients (50% male, mean age 63.17±10.18 years) with left ventricular ejection fraction <40% and 27 controls (44% male, mean age 61.33±8.73 years) were included in this study. Patients with CHF were divided into two groups as ischemic heart failure (IHF) and non-ischemic heart failure (NIHF) according to the underlying etiology. Plasma CHIT and N-terminal pro brain natriuretic peptide (NT-proBNP) levels were measured by ELISA method. Plasma CHIT and NT-proBNP levels were higher in patients with CHF than in controls (CHIT 931.25±461.39 ng/mL, 232.79±61.28 ng/mL, p<0.001; NT-proBNP, 595.31±428.11 pg/mL vs 78.13±30.47 pg/L; p<0.001). Also, the levels of these parameters increased in IHF compared with NIHF (CHIT, 1139.28±495.22 ng/mL, 671.22±237.21 ng/mL, p=0.002; NT-proBNP, 792.87±461.26 pg/mL vs 348.36±202.61 pg/mL, p=0.001) and there was a strong correlation between NT-proBNP and CHIT (r=0.969, p<0.001). According to this study findings, plasma CHIT level increases in CHF and its increased levels are correlated with NT-proBNP which is used diagnosis and prognosis of HF.

Overproduction of mucus and impaired clearance play important roles in the pathogenesis of muco-obstructive lung diseases (MOLDs). This study aims to evaluate the therapeutic effect and safety of nebulized hypertonic saline (HS) on MOLDs. Five electronic databases including PubMed, Excerpt Medica Database (EMBASE), Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and International Standard Randomized Controlled Trial Number Register were searched until June 2019. Randomized controlled trials or randomized controlled crossover trials which investigated the therapeutic effect of HS versus non-HS for MOLDs were included. Twenty-one studies met the eligibility criteria. For cystic fibrosis (CF), although the forced expiratory volume in the first second and forced vital capacity did not improve significantly (mean difference (MD) −0.48, 95% CI −3.72 to 2.76), (MD 1.85, 95% CI −4.31 to 8.01), respectively), the clearance capability of lung and quality of life (QOL) improved significantly in the HS group ((standard mean difference 0.44, 95% CI 0.02 to 0.87), (MD −0.64, 95% CI −)1.14, to 0.13), respectively). However, the results of trial sequential analysis showed the evidence needed more researches to support. The effect of nebulized HS on non-CF bronchiectasis, chronic obstructive pulmonary disease, and primary ciliary dyskinesia also need more evidence to conclude, since current studies are limited and results are inconsistent. Most adverse events of nebulized HS were mild and transient. In summary, the current available evidence suggests that nebulized HS may increase the QOL in CF, but there was no significant improvement in lung function. However, it is not possible to draw firm conclusions for other MOLDs due to limited data.

Cardiomyocyte hypertrophy is a response to stress or hormone stimulation and is characterized by an increase of cardiomyocyte size. Abnormal long non-coding RNA (lncRNA) expression profile has been identified in various cardiovascular diseases. Though some lncRNAs had been reported to participate in regulation of cardiac hypertrophy, the universal lncRNA profile of cardiomyocyte hypertrophy had not been established. In the present study, we aimed to identify the differentially expressed lncRNA-mRNA network in angiotensin II-stimulated cardiomyocytes, and screen the potential lncRNAs involved in regulation of cardiomyocyte hypertrophy. The hypertrophic cardiomyocytes were induced by angiotensin II (0.1 μmol/L) for 48 hours. High-throughput microarray analysis combined with quantitative real-time PCR assay were then performed to screen the differentially expressed lncRNAs and mRNAs. A total of 1577 lncRNAs and 496 mRNAs transcripts were identified differentially expressed in hypertrophic cardiomyocytes. Among them, 59 transcribed ultraconserved non-coding RNAs (T-UCRs) were found by evolutionary conservation analysis. Subsequently, the lncRNA-mRNA coexpression network was constructed based on Pearson's correlation analysis results, including 4 T-UCRs and 215 mRNAs. The results revealed that uc.242 was positively interacted with prohypertrophic genes (Hgf and Tnc). Functional study showed that inhibition of uc.242 dramatically decreased hypertrophic marker expression levels and cardiomyocyte surface area under the condition of angiotensin II stimulation. The expression of Hgf and Tnc was also decreased in cardiomyocytes after silencing of uc.242. Summarily, the present study provided crucial clues to explore therapeutic targets for pathological cardiac hypertrophy.

In patients with infective endocarditis (IE), ST-elevation myocardial infarction (STEMI) is an uncommon phenomenon. Due to limited data, we intend to evaluate the clinical outcomes in hospitalized patients with STEMI with and without underlying IE. Mortality and morbidity are exponentially worse in STEMI with concomitant IE when compared with without IE. Patients with primary diagnosis of STEMI with and without IE were identified by querying the Healthcare Cost and Utilization Project database of the National Inpatient Sample for the years 2013 and 2014 based on International Classification of Diseases, Ninth Revision codes. During 2013 and 2014, a total of 117,386 patients were admitted with the principle diagnosis of STEMI, out of whom 305 had comorbid IE. There was a significantly increased in-hospital mortality (27.5% vs 10.8%), length of stay (LOS) (14 days vs 5 days), acute kidney injury (AKI; 44.9% vs 18.7%), stroke (23.6% vs 3%), aortic valve replacement (9.5% vs 0.3%), mitral valve replacement (0.2%-5.2%), sepsis (50% vs 6%) and acute respiratory failure (36.7% vs 16.7%) in patients with STEMI with IE when compared with patients with STEMI and without comorbid IE. STEMI without IE had a higher number of angiographies (58.7% vs 25.9%) and percutaneous coronary interventions (50.7% vs 14.4%) during the hospital course when compared with STEMI with IE. In conclusions, hospitalized patients with STEMI with a concurrent diagnosis of IE are at higher risk of in-hospital mortality, increased LOS, AKI, stroke, valve replacements, and acute respiratory failure.

The present study sought to investigate the association between silent information regulator 1 (SIRT1) and autophagy during systemic inflammatory response syndrome following burn injury. The experimental burn model in mice and macrophages were established. SIRT1 mRNA expression was quantified by quantitative real-time PCR. The protein levels of SIRT1 and the conversion of light chain 3 (LC3)-I to LC3-II were determined by western blot analysis. The formation of autophagosomes was assessed by green fluorescence protein-tagged LC3 fluorescence. The contents of inflammatory cytokines interleukin (IL)-1, IL-6, IL-10 and IL-18 were measured by ELISA. SIRT1 was highly expressed in burned tissues and RAW264.7 cells treated with serum obtained from mice with burn injuries. Moreover, SIRT1 overexpression augmented, whereas sirtinol, an inhibitor of SIRT1, attenuated burn injury-induced increasing number of autophagosomes and expression levels of LC3-II/LC3-I in RAW264.7 cells. Besides, sirtinol effectively prevented SIRT1-induced pro-inflammation during burn injury. Furthermore, autophagy inhibition by 3-methyladenine significantly attenuated SIRT1 overexpression-mediated pro-inflammatory cytokine production. SIRT1 abolished burn injury-induced inflammatory response by inducing autophagy.

Circular RNA (circRNA) is an endogenous RNA molecule with a stable closed-loop structure. The circular RNA HIPK3 (circHIPK3) is highly expressed in hepatocellular carcinoma and facilitates tumor growth. However, its role in cervical cancer (CC) and its regulatory mechanisms are not well-studied. This study aimed for investigating the function of circHIPK3 on proliferation and metastasis of CC cells. In this study, quantitative real-time PCR assay was adopted to delve into the circHIPK3 expression in CC cell lines. Cell counting kit-8 and colony formation assays were used to evaluate the influence of overexpression and knockdown of circHIPK3 on CC cell proliferation. Dual-luciferase reporter assay was employed to probe into the binding of miR-485-3p to circHIPK3 and miR-485-3p to the 3’ untranslated region (UTR) of fibroblast growth factor 2 (FGF2), respectively. FGF2 protein expression was detected by western blot analysis. This study confirmed that circHIPK3 was highly expressed in CC tissues. Overexpressed circHIPK3 could remarkably expedite the proliferation, migration and invasion of SiHa cells, and knocking down circHIPK3 could significantly impede the proliferation, migration and invasion of HeLa cells. MiR-485-3p can directly bind to circHIPK3 and the 3'UTR of FGF2. Overexpression of circHIPK3 triggered the upregulation of FGF2 expression while knockdown of circHIPK3 reduced FGF2 expression in CC cells, and the transfection of miR-485-3p mimics reversed the upregulation of FGF2 expression and enhanced malignant phenotypes in CC cells with overexpressed circHIPK3.

Health science researchers need training and support to effectively pursue independence in their research careers. Little data exist regarding the specific resources that faculty researchers have found or would find useful. In this study, we aimed to better understand the needs of health science researchers to develop recommendations for effective career development programming. The authors conducted a multi-method evaluation of early-career researcher faculty needs beginning by using post-session satisfaction surveys to assess the value of a long-standing “K-Club” seminar, which educates and supports those pursuing NIH Career Development (K) awards or similar. The authors then collected in-depth views on career development needs through a series of focus groups conducted with health science researchers at three career stages: early career, award-seeking junior faculty; mid-career faculty who have obtained some extramural funding; senior faculty who serve as mentors for early/mid-career faculty. Participants who attended the existing K-Club strongly endorse the program in supporting their career goals. Focus group participants described specific areas for program expansion that would add value across career stages: more flexible training options, conducted in smaller group settings with immediate feedback provided; more formalized training and resources for senior research mentors; in-depth guidance on individualized grantsmanship. The authors propose program development guidelines for helping researchers achieve research independence and success. Findings indicate that a broad-reaching K-Club style educational seminar can serve as a valuable foundation supporting professional development. The addition of tailored programs delivered across diverse platforms are predicted to heighten career development success.

Medical conditions requiring treatment with anticoagulation (AC) or antiplatelet therapy have a huge burden on the average patient, but such conditions can have catastrophic effects on the careers of young, rising athletes, in particular those involved in contact sports at a professional level. Contact sports are defined as sports in which body-to-body contact is expected as part of the game such as football, basketball, soccer and hockey. The rates of injuries in these sports are high increasing the likelihood of bleeding event on AC. The main etiologies requiring AC and antiplatelets in athletes are venous thromboembolism and coronary artery disease, respectively. To date, there are no clear medical guidelines on the management of such conditions in athletes. Herein we review the traditional approach to treating such conditions afflicting athletes as well as more recently modified approaches to answer the ultimate question: should anticoagulation or antiplatelet therapy in contact sports be career limiting?

Permanent hypoparathyroidism is an endocrine disease that is mostly associated with the disruption of the parathyroid glands during surgery. Allotransplantation is the most promising approach for treatment particularly for its cost-effective and exact curative potential. Herein our aim was to evaluate human leukocyte antigen (HLA)-A allele matching effect on clinical improvement and graft survival after parathyroid transplantation. We performed parathyroid transplantation between ABO/Rh compatible recipient and an unrelated donor who has chronic kidney disease. Preoperative immunological tests include panel reactive antibody, T-flow cytometry crossmatch, B-flow cytometry crossmatch, autoflow cytometry crossmatch, and complement-dependent cytotoxicity crossmatch tests were performed. After histopathological evaluation, half of the resected parathyroid gland cells were isolated and transplanted to the omentum surface by laparoscopy. The transplantation outcome was followed up throughout 382 days. The recipient discharged 2 days after transplantation without any complication. During follow-up, calcium and vitamin D supplementation reduced to a one-third dose; even the intact PTH levels remained low. However, clinical improvement was observed by serum calcium levels. The recipient still continues with low-dose supplementation after 382 days of post-transplantation. Parathyroid cell transplantation to the omental tissue is the most promising option even with only one allele matching for patients with using lifelong high-dose supplementation. Clinical improvements and long-term effect of HLA-A allele matching should be evaluated with more studies and in larger cohorts as well.

Meckel's diverticulum (MD) is a well-defined diagnosis in children presenting with either bleeding or obstruction. Although anecdotally adult patients may present with complications from MD, their presentation seems to be different, with a reported predominance of non-bleed-related presentations. Reports in this population, however, are limited, and little is known of the epidemiology of MD in older patients. We performed a retrospective analysis of the Agency of Healthcare Research and Quality National Inpatient Sample of all US hospital discharges from 2012 to 2016. We identified patients with a primary discharge diagnosis of MD. Data were abstracted as raw numbers and population weighted rates of discharge with age group, income level, length of stay (LOS) and hospital charges as additional information. On average, 2030 individuals were discharged annually; most (71.1%) were adults (>18 years). Although MD was predominant in males in all age groups, the gender ratio decreased with older age categories from 3.5:1.0 (1-17 years) to 1.6:1.0 (65-84 years). LOS averaged 5.3 days with no clear relationship to other parameters. Median income category, however, closely correlated (R²=0.9996) with diagnosis in older age categories. MD may be significantly more prevalent in adult patients than was previously understood. Differences in gender preponderance suggest that gender may influence the pattern of presentation. Diagnosis in older individuals is closely associated with income or socioeconomic status but not hospital charges or LOS.