Three novel umami peptides derived from the alcohol extract of the Pacific oyster(Crassostrea gigas):identification,characterizations and interactions with T1R1/T1R3 taste receptors

Oyster(Crassostrea gigas),the main ingredient of oyster sauce,has a strong umami taste.In this study,three potential umami peptides,FLNQDEEAR(FR-9),FNKEE(FE-5),and EEFLK(EK-5),were identified and screened from the alcoholic extracts of the oyster using nano-HPLC-MS/MS analysis,i Umami-Scoring Card Method(i Umami-SCM)database and molecular docking(MD).Sensory evaluation and electronic tongue analysis were further used to confirm their tastes.The threshold of the three peptides ranged from 0.38 to 0.55 mg/m L.MD with umami receptors T1R1/T1R3 indicated that the electrostatic interaction and hydrogen bond interaction were the main forces involved.Besides,the Phe592 and Gln853 of T1R3 were the primary docking site for MD and played an important role in umami intensity.Peptides with two Glu residues at the terminus had stronger umami,especially at the C-terminus.These results contribute to the understanding of umami peptides in oysters and the interaction mechanism between umami peptides and umami receptors.

Long-term outcomes of endoscopic submucosal dissection for undifferentiated type early gastric cancer over 2 cm with R0 resection

BACKGROUND Endoscopic submucosal dissection(ESD)for over 2 cm in size undifferentiated type(UD type)early gastric cancer(EGC)confined to the mucosa is not only challenging,but also long-term outcomes are not well known.AIM To evaluate the long-term outcomes of ESD done for UD type EGCs confined to the mucosa over 2 cm in size and compare the results with those where the lesions were less than 2 cm.METHODS 143 patients with UD type EGC confirmed on histology after ESD at a tertiary hospital were reviewed.Cases with synchronous and metachronous lesions and a case with emergency surgery after ESD were excluded.A total of 137 cases were enrolled.79 cases who underwent R0 resection were divided into 2 cm or less(group A)and over 2 cm(group B)in size.RESULTS Among 79 patients who underwent R0 resection,the number in group A and B were 51 and 28,respectively.The mean follow-up period(SD)was 79.71±45.42 months.There was a local recurrence in group A(1/51,2%)and group B(1/28,3.6%)respectively.This patient in group A underwent surgery while the patient in group B underwent repeated ESD with no further recurrences in both patients.There was no regional lymph node metastasis,distant metastasis,and deaths in both groups.With R0 resection strategy for ESD on lesions over 2 cm,20.4%(28/137)of patients were able to avoid surgery compared with expanded indication.CONCLUSION If R0 resection is achieved by ESD,UD type EGCs over 2 cm also showed good and similar clinical outcomes as compared to lesions less than 2 cm when followed for over 5 years.With R0 resection strategy,several patients can avoid surgery.

Point-of-care ultrasonography in cirrhosis-related acute kidney injury:How I do it

Discerning the etiology of acute kidney injury(AKI)in cirrhotic patients remains a formidable challenge due to diverse and overlapping causes.The conventional approach of empiric albumin administration for suspected volume depletion may inadvertently lead to fluid overload.In the recent past,point-of-care ultrasonography(POCUS)has emerged as a valuable adjunct to clinical assessment,offering advantages in terms of diagnostic accuracy,rapidity,cost-effectiveness,and patient satisfaction.This review provides insights into the strategic use of POCUS in evaluating cirrhotic patients with AKI.The review distinguishes basic and advanced POCUS,emphasizing a 5-point basic POCUS protocol for efficient assessment.This protocol includes evaluations of the kidneys and urinary bladder for obstructive nephropathy,lung ultrasound for detecting extravascular lung water,inferior vena cava(IVC)ultrasound for estimating right atrial pressure,internal jugular vein ultrasound as an alternative to IVC assessment,and focused cardiac ultrasound for assessing left ventricular(LV)systolic function and identifying potential causes of a plethoric IVC.Advanced POCUS delves into additional Doppler parameters,including stroke volume and cardiac output,LV filling pressures and venous congestion assessment to diagnose or prevent iatrogenic fluid overload.POCUS,when employed judiciously,enhances the diagnostic precision in evaluating AKI in cirrhotic patients,guiding appropriate therapeutic interventions,and minimizing the risk of fluid-related complications.

Prediabetes: An overlooked risk factor for major adverse cardiac and cerebrovascular events in atrial fibrillation patients

BACKGROUND Prediabetes is a well-established risk factor for major adverse cardiac and cerebrovascular events(MACCE).However,the relationship between prediabetes and MACCE in atrial fibrillation(AF)patients has not been extensively studied.Therefore,this study aimed to establish a link between prediabetes and MACCE in AF patients.AIM To investigate a link between prediabetes and MACCE in AF patients.METHODS We used the National Inpatient Sample(2019)and relevant ICD-10 CM codes to identify hospitalizations with AF and categorized them into groups with and without prediabetes,excluding diabetics.The primary outcome was MACCE(all-cause inpatient mortality,cardiac arrest including ventricular fibrillation,and stroke)in AF-related hospitalizations.RESULTS Of the 2965875 AF-related hospitalizations for MACCE,47505(1.6%)were among patients with prediabetes.The prediabetes cohort was relatively younger(median 75 vs 78 years),and often consisted of males(56.3%vs 51.4%),blacks(9.8%vs 7.9%),Hispanics(7.3%vs 4.3%),and Asians(4.7%vs 1.6%)than the non-prediabetic cohort(P<0.001).The prediabetes group had significantly higher rates of hypertension,hyperlipidemia,smoking,obesity,drug abuse,prior myocardial infarction,peripheral vascular disease,and hyperthyroidism(all P<0.05).The prediabetes cohort was often discharged routinely(51.1%vs 41.1%),but more frequently required home health care(23.6%vs 21.0%)and had higher costs.After adjusting for baseline characteristics or comorbidities,the prediabetes cohort with AF admissions showed a higher rate and significantly higher odds of MACCE compared to the non-prediabetic cohort[18.6%vs 14.7%,odds ratio(OR)1.34,95%confidence interval 1.26-1.42,P<0.001].On subgroup analyses,males had a stronger association(aOR 1.43)compared to females(aOR 1.22),whereas on the race-wise comparison,Hispanics(aOR 1.43)and Asians(aOR 1.36)had a stronger association with MACCE with prediabetes vs whites(aOR 1.33)and blacks(aOR 1.21).CONCLUSION This population-based study found a significant association between prediabetes and MACCE in AF patients.Therefore,there is a need for further research to actively screen and manage prediabetes in AF to prevent MACCE.

Unlocking hypoglycemia–associated brain microvascular dysfunction:critical insights from proteomic analysis

Hypoglycemia-a critical complication linked to worsened brain function in diabetic subjects:Hypoglycemia is characterized by a decline in circulatory glucose levels below sta nda rd physiological thresholds.Mild hypoglycemia,classified as level 1 hypoglycemia,is defined by blood glucose levels below 70 mg/dL and can be effectively addressed through carbohydrate intake.Severe hypoglycemia,denoted by blood glucose levels less than 54 mg/dL,poses a life-threatening risk if left untreated.Individuals with type 1 and type 2 diabetes undergoing insulin treatment are particularly susceptible to hypoglycemia due to impaired counterregulatory mechanisms.

Role of copper transporters in platinum resistance

Platinum(Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1(CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7 A and ATP7 B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.

An unusual cause of dyspnoea complicating right upper abdominal swelling

A middle aged, non-addict male presented with right upper abdominal pain and swelling with respiratory distress. Examination revealed central cyanosis, bipedal pitting edema with prominent epigastric and back veins. Liver was enlarged, tender, spanned 20 cm without any splenomegaly or ascites. Other systems were clinically normal. Laboratory investigations showed polymorphonuclear leucocytosis with slightly deranged liver function. Abdominal ultrasonography showed an abscess in the right lobe of the liver with compressed inferior vena cava （IVC）, middle and left hepatic veins. Arterial blood gas （ABG） documented hypoxia with orthodeoxia and air-contrast echocardiography was suggestive of an intrapulmonary shunt. A diagnosis of hepato-pulmonary syndrome （HPS） was made with near normal liver function secondary to amebic liver abscess. It reversed completely following successful treatment of the liver abscess.

Hemodynamic effects of propranolol with spironolactone in patients with variceal bleeds: A randomized controlled trial

AIM: To study the hemodynamic effects of spironolactone with propranolol vs propranolol alone in the secondary prophylaxis of variceal bleeding. METHODS: Thirty-five cirrhotics with variceal bleeding randomly received propranolol (n = 17: Group A) or spironolactone plus propranolol (n = 18: Group B). Hemodynamic assessment was performed at baseline and on the eighth day. RESULTS: Spironolactone with propranolol caused a greater reduction in the hepatic venous pressure gradient than propranolol alone (26.94% vs 10.2%; P < 0.01). Fourteen out of eighteen patients on the combination treatment had a reduction in hepatic venous pressure gradient to ≤ 12 mmHg or a 20% reduction from baseline in contrast to only six out of seventeen (6/17) on propranolol alone (P < 0.05). CONCLUSION: Spironolactone with propranolol results in a better response with a greater reduction in hepatic venous pressure gradient in the secondary prophylaxis of variceal bleeding. A greater number of patients may be protected by this combination therapy than by propranolol alone. Hence, this combination may be recommended for secondary prophylaxis in patients with variceal bleeding.

A Simple Approach of Low Back Pain

Low back pain (LBP) is primarily managed in general practice and commonly underestimated or misdiagnosed by physicians. This article presents comprehensive review for diagnosis and evaluation of LBP according to current clinical studies guidelines. Our objectives are to define LBP, to establish how to take a detailed history and how to physically examine it in order to enable physicians to make an appropriate differential diagnosis for LBP, and to identify relevant investigations and referrals of patients with LBP. The article first offers a quick description of inflammatory back pain then discusses the importance of screening red flag patients with LBP and the importance of its early detection. Finally, we summarize how to outline a primary plan for managing and treating LBP. The article is prepared in the format of question and answer to make it targeted and accessible.

Pentoxifylline versus prednisolone for severe alcoholic hepatitis:A randomized controlled trial

AIM： To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis, and to evaluate the role of different liver function scores in predicting prognosis.METHODS： Sixty-eight patients with severe alcoholic hepatitis （Maddrey score ≥ 32） received pentoxifylline （n = 34, group Ⅰ） or prednisolone （n = 34, group Ⅱ） for 28 d in a randomized double-blind controlled study, and subsequently in an open study （with a tapering dose of prednisolone） for a total of 3 mo, and were followed up over a period of 12 mo.RESULTS： Twelve patients in group Ⅱ died at the end of 3 mo in contrast to five patients in group Ⅰ. The probability of dying at the end of 3 mo was higher in group Ⅱ as compared to group Ⅰ （35.29% vs 14.71%, P = 0.04; log rank test）. Six patients in group I developed hepatorenal syndrome as compared to none in group Ⅰ. Pentoxifylline was associated with a significantly lower model for end-stage liver disease （MELD） score at the end of 28 d of therapy （15.53± 3.63 vs 17.78± 4.56, P=0.04）. Higher baseline Maddrey score was associated with increased mortality.CONCLUSION： Reduced mortality, improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis.

Novel concepts in radiation-induced cardiovascular disease

Radiation-induced cardiovascular disease(RICVD) is the most common nonmalignant cause of morbidity and mortality among cancer survivors who have undergone mediastinal radiation therapy(RT).Cardiovascular complications include effusive or constrictive pericarditis,cardiomyopathy,valvular heart disease,and coronary/vascular disease.These are pathophysiologically distinct disease entities whose prevalence varies depending on the timing and extent of radiation exposure to the heart and great vessels.Although refinements in RT dosimetry and shielding will inevitably limit future cases of RICVD,the increasing number of long-term cancer survivors,including those treated with older higher-dose RT regimens,will ensure a steady flow of afflicted patients for the foreseeable future.Thus,there is a pressing need for enhanced understanding of the disease mechanisms,and improved detection methods and treatment strategies.Newly characterized mechanisms responsible for the establishment of chronic fibrosis,such as oxidative stress,inflammation and epigenetic modifications,are discussed and linked to potential treatments currently under study.Novel imaging modalities may serve as powerful screening tools in RICVD,and recent research and expert opinion advocating their use is introduced.Data arguing for the aggressive use of percutaneous interventions,such as transcutaneous valve replacement and drug-eluting stents,are examined and considered in the context of prior therapeutic approaches.RICVD and its treatment options are the subject of a rich and dynamic body of research,and patients who are at risk or suffering from this disease will benefit from the care of physicians with specialty expertise in the emerging field of cardiooncology.

Hepatic failure caused by plasma cell infiltration in multiple myeloma

Although plasma cell infiltration is not rare in autopsy of patients with multiple myeloma （MM）, it is very rarely detected in living patients. This is because MM rarely causes significant liver dysfunction that requires further evaluation. A 49-year-old man presented with acute renal failure and was diagnosed with kappa light chain MM stageⅡB. Thalidomide and dexamethasone were initiated. The patient developed a continuous increase in bilirubin that led to severe cholestasis. A liver biopsy revealed plasma cell infiltration. He then rapidly progressed to liver failure and died. Treatment options are limited in MM with significant liver dysfunction. Despite new drug therapies in MM, those patients with rapidly progressive liver failure appear to have a dismal outcome.

The relationship between anxiety about prostate cancer among patients with biochemical cancer recurrence and the use of complementary and alternative medicines,diet,and exercise

Objective:We aimed to explore associations between anxiety and specific health behaviors such as complementary and alternative medicine(CAM),diet,and exercise among prostate cancer patients.Methods:PCa patients enrolled in a prospective cohort study of men with biochemical cancer recurrence were surveyed about use of CAM,diet,and exercise.Anxiety was measured with the Memorial Anxiety Scale for Prostate Cancer(MAX-PC)and the anxiety subscale of the Hospital Anxiety and Depression Scale.Results:Nearly 70%(44 of 67)of the original cohort of patients completed the supplementary CAM survey.The mean age was 68 years.Eighty percent of respondents reported engaging in a rel-evant health behavior,and 64%reported doing so in direct response to their PCa diagnosis.Overall,the most prevalent specific behaviors were exercising(56%),making dietary changes(50%),taking calcium supplements(41%),and taking vitamin D supplements(39%).Elevated baseline PCa-specific anxiety(MAX-PC score>16)after biochemical cancer recurrence was associated with use of any CAM(P=0.01),use of herbs/supplements(P=0.01),and dietary changes(P=0.04).Conclusion:PCa patients commonly use CAM,dietary changes,and exercise in response to their diagnosis,and these changes are associated with elevated general and PCa-specific anxiety.

LBP–Bilateral Based Feature Fusion for Breast Cancer Diagnosis

Since reporting cases of breast cancer are on the rise all over the world.Especially in regions such as Pakistan,Saudi Arabia,and the United States.Efficient methods for the early detection and diagnosis of breast cancer are needed.The usual diagnosis procedures followed by physicians has been updated with modern diagnostic approaches that include computer-aided support for better accuracy.Machine learning based practices has increased the accuracy and efficiency of medical diagnosis,which has helped save lives of many patients.There is much research in the field of medical imaging diagnostics that can be applied to the variety of data such as magnetic resonance images(MRIs),mammograms,X-rays,ultrasounds,and histopathological images,but magnetic resonance(MR)and mammogram imaging have proved to present the promising results.The proposed paper has presented the results of classification algorithms over Breast Cancer(BC)mammograms from a novel dataset taken from hospitals in the Qassim health cluster of Saudi Arabia.This paper has developed a novel approach called the novel spectral extraction algorithm(NSEA)that uses feature extraction and fusion by using local binary pattern(LBP)and bilateral algorithms,as well as a support vector machine(SVM)as a classifier.The NSEA with the SVM classifier demonstrated a promising accuracy of 94%and an elapsed time of 0.68 milliseconds,which were significantly better results than those of comparative experiments from classifiers named Naïve Bayes,logistic regression,K-Nearest Neighbor(KNN),Gaussian Discriminant Analysis(GDA),AdaBoost and Extreme Learning Machine(ELM).ELM produced the comparative accuracy of 94%however has a lower elapsed time of 1.35 as compared to SVM.Adaboost has produced a fairly well accuracy of 82%,KNN has a low accuracy of 66%.However Logistic Regression,GDA and Naïve Bayes have produced the lowest accuracies of 47%,43%and 42%.

Breast Cancer Detection in Saudi Arabian Women Using Hybrid Machine Learning on Mammographic Images

Breast cancer(BC)is the most common cause of women’s deaths worldwide.The mammography technique is the most important modality for the detection of BC.To detect abnormalities in mammographic images,the Breast Imaging Reporting and Data System(BI-RADs)is used as a baseline.The correct allocation of BI-RADs categories for mammographic images is always an interesting task,even for specialists.In this work,to detect and classify the mammogram images in BI-RADs,a novel hybrid model is presented using a convolutional neural network(CNN)with the integration of a support vector machine(SVM).The dataset used in this research was collected from different hospitals in the Qassim health cluster of Saudi Arabia.The collection of all categories of BI-RADs is one of the major contributions of this paper.Another significant contribution is the development of a hybrid approach through the integration of CNN and SVM.The proposed hybrid approach uses three CNN models to obtain ensemble CNN model results.This ensemble model saves the values to integrate them with SVM.The proposed system achieved a classification accuracy,sensitivity,specificity,precision,and F1-score of 93.6%,94.8%,96.9%,96.6%,and 95.7%,respectively.The proposed model achieved better performance compared to previously available methods.

Engineering T cells for immunotherapy of primary human hepatocellular carcinoma

Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes(TCRTs) and the chimeric antigen receptor genes(CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.

Clinical analysis of massive hemispheric infarction treated with moderate hypothermia

The potential of hypothermia in reducing neuronal damage has beendemonstrated in several animal models of focal cerebral ischemia. The feasibility and safety ofthis technique for acute stroke has been only examined in one study, describing a total of 25patients. We analyzed the data from 50 consecutive patients with acute stroke treated with moderatehypothermia in neurocritical care units of 4 university clinics to evaluate the feasibility andsafety of moderate hypothermia.

The efficacy of rapid on-site evaluation during endoscopic ultrasound-guided fine needle aspiration of pancreatic masses

Background:Endoscopic ultrasound(EUS)-guided fine needle aspiration(FNA)has become the preferred method to diagnose pancreatic masses due to its minimally invasive approach and diagnostic accuracy.Many studies have shown that rapid on-site evaluation(ROSE)improves diagnostic yield by 10–30%;however,more recent studies have demonstrated effective diagnostic accuracy rates without ROSE.Our study aims to examine whether the current standard of performing ROSE after each FNA pass adds diagnostic value during EUS-guided FNA of pancreatic masses.Methods:We conducted a retrospective case series on patients who underwent EUS-guided FNA of pancreatic masses between February 2011 and October 2014.All cases were performed by one of three endoscopists at Emory University Hospital.Patient demographics,radiologic details of pancreatic masses and pathology reports of the biopsied pancreatic masses were examined.Results:A total of 184 procedures performed in 171 patients were reviewed.The final pathology reports of the biopsied pancreatic masses showed 128(70%)with confirmed malignancy.Only 64(50%)of these 128 cases initially showed malignant cells during ROSE.Among these 64 cases,23%required 5 or more FNA passes to first detect malignant cells.Conclusions:The use of ROSE during EUS-guided FNA of pancreatic masses may increase the diagnostic yield,since malignant cells were often detected during later FNA passes that would otherwise be missed if tissue sampling stopped prematurely.In addition,sample preparation for ROSE may be suboptimal,since malignant cells were only detected in 50%of cases.

S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission

Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.