Molecular insights and promise of oncolytic virus based immunotherapy.

Discovering a therapeutic that can counteract the aggressiveness of this disease's mechanism is crucial for improving survival rates for cancer patients and for better understanding the most different types of cancer. In recent years, using these viruses as an anticancer therapy has been thought to be successful. They mostly work by directly destroying cancer cells, activating the immune system to fight cancer, and expressing exogenous effector genes. For the treatment of tumors, oncolytic viruses (OVs), which can be modified to reproduce only in tumor tissues and lyse them while preserving the healthy non-neoplastic host cells and reinstating antitumor immunity which present a novel immunotherapeutic strategy. OVs can exist naturally or be created in a lab by altering existing viruses. These changes heralded the beginning of a new era of less harmful virus-based cancer therapy. We discuss three different types of oncolytic viruses that have already received regulatory approval to treat cancer as well as clinical research using oncolytic adenoviruses. The primary therapeutic applications, mechanism of action of oncolytic virus updates, future views of this therapy will be covered in this chapter.

Outpatient Clinical Markers for Laryngopharyngeal Reflux Disease: A Correlational Study.

Laryngopharyngeal reflux disease (LPRD) is the result of retrograde flow of gastric contents to the laryngopharynx which comes in contact with tissues of the upper aerodigestive tract. Due to ill defined criteria for diagnosis & followup, LPRD patients are underdiagnosed & undertreated. Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS) are two clinical methods which can be utilised especially in the outpatient setup. This study was done with the aim to assess various laryngoscopic findings in patients with LPRD diagnosed symptomatically and examine the correlation between the RSI & RFS by comparing these two indices. This prospective analytical study was conducted at a tertiary care centre in Bangalore in the Department of ENT for a period of 24 months between Dec 2020 to Dec 2022. The study included patients aged 18 to 60 years diagnosed with LPRD based on symptoms as per RSI score (> 13). RSI & RFS were assessed on diagnosis and patients were followed up for 1, 3 & 6 months for assessment. Total 96 patients were enrolled, with mean age of be 42.49 ± 11.33 years. Prevalence was found to be more in females (61.5%). The most common symptom according to RSI was frequent throat clearing & globus sensation (sensation of something sticking in throat) and most common finding according to RFS was erythema/hyperemia. The mean score of RSI and RFI was found to reduce with treatment at different intervals in follow-up visits. There was a significant strength of association between the RSI and RFS at baseline, 1st month, 3rd month and 6th month of follow-up (r = 0.568, r = 0.684, r = 0.774, r = 0.736 respectively) (p < 0.001).The RFS and RSI showed statistically significant strong relationships between total scores and sign and symptom characteristics. On follow-up, there was a significant reduction in the RSI which was also correlated with a reduction in RFS.

Intra-Operative Dermoscopy in Assessment of Melanonychia and as a Guide for Biopsy.

BACKGROUND AND AIMS: Melanonychia can be a manifestation of benign or malignant pathology and often poses a diagnostic challenge on clinical examination. Even with distinguishing dermoscopic features (nail plate), it can be quite difficult to determine the nature of pigmentation as complete assessment of nail bed and matrix is still not possible. Intraoperative dermoscopy (IOD) can serve as a useful tool to appreciate the bed and matrix changes. The aim here is to study the intraoperative dermoscopic features in patients with melanonychia and correlate with histopathology. METHODS: 20 consecutive patients with melanonychia were recruited. Inclusion criteria was melanonychia of sudden onset, progressive nature, irregular width/color/symmetry on dermoscopy, positive Hutchinson sign, solitary nail involvement or associated nail dystrophy. Preoperative dermoscopy was performed and recorded. Patients were planned for nail matrix biopsy, during which IOD was performed over nail matrix and bed after removal of the nail plate. Images were recorded and analyzed and correlated with the histopathology. RESULTS: Out of 20 patients, 12 were females and 8 males. On IOD-histopathological correlation, 2 patients were found to have melanoma of the nail unit, 5had nail lichen planus, 9 had benign melanocytic nevi, and 4 had fungal melanonychia. IOD revealed fine, parallel and regular lines of pigmentation localized to proximal nail bed and matrix in all patients with benign melanonychia, while dark thick bands with irregular borders, dots, globules, streaks and structureless areas in the two patients with melanoma. Fungal melanonychia revealed an unremarkable nail bed and matrix on IOD. CONCLUSION: Intraoperative dermoscopycan help in determining the nature of melanonychia and obviate the need to perform biopsy in certain cases. It can also aid in delineating the most suitable site for biopsy, along with grossly assessing the extent of involvement in case of malignancy.

Primary Yolk Sac Tumor of the Liver in an Adult Man.

Primary yolk sac tumor of the liver is extremely rare in adults. We report a case of a young man with an unresectable primary yolk sac tumor of the liver, who had a platinum-refractory disease that progressed despite 2 lines of chemotherapy. We review the literature pertaining to primary yolk sac tumor of the liver and its management.

Ruthenium Chloride-Induced Oxidative Cyclization of Trans-Resveratrol to (±)-ε-Viniferin and Antimicrobial and Antibiofilm Activity Against Streptococcus pneumoniae.

Polyphenol ε-viniferin (2) is a protective phytochemical found in several plant families. Here, we report a simple and effective method for the synthesis of (±)-ε-viniferin (2) as major product and (±)-(E)-ω-viniferin (3) as a minor product. Synthesized viniferin compounds and standard viniferin were analyzed for antibacterial and antibiofilm activity against Gram-positive bacteria Streptococcus pneumoniae. The minimum inhibitory concentrations (MICs) of (±)-ε-viniferin (2) and standard viniferin were 20 µm. However, the MICs of (±)-(E)-ω-viniferin (3) and compound 8 were 40 µm. Although viniferin significantly (p < 0.05) reduced pre-established in vitro biofilms and killed bacteria within the biofilm, it was unable to prevent biofilm formation at sub-MIC concentrations. The time kill experiment revealed that viniferin killed bacteria and reduced 2.8 log10 bacteria at 2 × MIC concentration after 24 h. Scanning electron microscope (SEM) analysis and live/dead biofilm staining of pre-established biofilms revealed that viniferin treatment disrupts membrane integrity of biofilm bacteria. Crystal violet absorption, total protein, and DNA and RNA release revealed that viniferin alters bacterial cell permeability, eventually killing bacteria.

In Vivo Toxicity Study of Ethanolic Extracts of Evolvulus alsinoides & Centella asiatica in Swiss Albino Mice.

AIM: We aimed to investigate several parameters after the in vivo acute and sub-acute administration of ethanolic extracts from E. alsinoides & C. asiatica. METHODS: Malignant Ovarian Germ Cell Tumors for in vivo toxicity study guidelines 423 and 407 of Organization for Economic Co-operation and Development (OECD) were followed for acute and sub-acute toxicity assays respectively. For LD50 evaluation, a single dose of ethanolic extracts of Evolvulus alsinoides L. (EEA) and ethanolic extracts of Centella asiatica (ECA) was orally administered to mice at doses of 200, 400, 800, 1600 and 2000 mg/kg. Then the animals were observed for 72 hours. For acute toxicity evaluation, a single dose of both extracts was orally administered to mice at doses of 300, 600, 1200 and 2000 mg/kg and the animals were observed for 14 days. In the sub-acute study, the extracts were orally administered to mice for 28 days at doses of 300, 600, 1200 and 2000 mg/kg. To assess the toxicological effects, animals were closely observed on general behaviour, clinical signs of toxicity, body weight, food and water intake. At the end of the study, it was performed biochemical and hematological evaluations, as well as histopathological analysis from the following organs: brain, heart, liver, and kidney. RESULTS: The oral administration of E. alsinoides and C. asiatica ethanolic extracts, i.e. EEA 300, EEA 600, EEA 1200, EEA 2000, ECA 300, ECA 600, ECA 1200 & ECA 2000 mg/kg doses showed no moral toxicity effect in LD50, acute and sub-acute toxicity parameters. CONCLUSION: In this study, we had found that E. alsinoides & C. asiatica extract at different doses cause no mortality in acute and sub-acute toxicity study. Also, histopathology of kidney, liver, heart, and brain showed no alterations in tissues morphology.

ESTIMATION OF RADIATION EXPOSURE TO THE PATIENTS IN DIAGNOSTIC AND THERAPEUTIC INTERVENTIONAL PROCEDURES.

The present work reports data of the radiation exposure to the patient in various diagnostic and therapeutic interventional radiological (IR) procedures. The study includes 260 diagnostic and 195 therapeutic exposure data in 455 IR procedures. All the IR procedures were performed on a biplane angiographic machine in a tertiary care hospital. The radiation exposure was estimated from dose-area product (DAP), fluoroscopy time (FT), number of fluoroscopic runs, number of images and cumulative dose (CD) value recorded during the procedure. The data reported in the present study show significant variability in DAP values in diagnostic and therapeutic IR procedures. In diagnostic procedures, the minimum median DAP value is 8.93 Gy cm2 for upper limb angiography with mean FT of 2.7 min and maximum DAP value is 108.8 Gy cm2 for inferior vena cava angiography with mean FT of 12.55 min. For therapeutic procedures, the median value of DAP ranges from 2.43 Gy cm2 for sclerotherapy with mean FT 0.65 min to 267.23 Gy cm2 for coiling of cerebral aneurysm with mean FT of 60.52 min. The DAP value for each procedure was also correlated with FT, number of fluoroscopic runs, number of images and CD. The reported DAP values in this study are within the range of earlier published results which suggest that our finding provides at least approximate applicability to other hospitals. The third quartile DAP values of the procedures having significant number of patient data (n ≥ 10) serves as provisional reference values for the optimization of procedure protocols.

Autologous bone marrow-derived mononuclear cells transplantation in type 2 diabetes mellitus: effect on ß-cell function and insulin sensitivity.

BACKGROUND: Insulin resistance and insulin deficiency are the cardinal defects in the pathogenesis of type 2 diabetes mellitus (T2DM). Despite the plethora of anti-diabetic medications, drugs specifically targeting the ß-cells are still desired. Stem cell therapy has emerged as a novel therapeutics strategy to target ß-cells; however, their mechanism of action has not been well defined. This study aims to examine the efficacy and safety of autologous bone marrow-derived mononuclear cells (ABM-MNCs) transplantation in T2DM, and explores the mechanistic insights into stem cells action through metabolic studies. METHODS: Seven T2DM patients with the duration of disease ≥5 years, receiving triple oral anti-diabetic drugs along with insulin (≥0.4 IU per kg per day) and HbA1c ≤ 7.5% (≤58.0 mmol/mol) were enrolled for ABM-MNCs administration through a targeted approach. The primary end-point was a reduction in insulin requirement by ≥50% from baseline, while maintaining HbA1c < 7.0% (<53.0 mmol/mol) with improvement in insulin secretion, and/or insulin sensitivity after ABM-MNCs transplantation. RESULTS: Six out of 7 (90%) patients achieved the primary end-point. At 6 months, there was a significant reduction in insulin requirement by 51% as compared to baseline (p < 0.003). This was accompanied by a significant increase in the 2nd phase C-peptide response during hyperglycemic clamp (p = 0.018), whereas there were no significant alterations in insulin sensitivity and glucose disposal rate during hyperinsulinemic-euglycemic clamp relative to the baseline. Other measures of ß-cell indices like HOMA-ß, and stimulated C-peptide response to glucagon and mixed meal tolerance test were non-contributory. CONCLUSION: ABM-MNCs transplantation results in significant reduction in insulin doses and improvement in C-peptide response in patients with T2DM. Metabolic studies may be more useful than conventional indices to predict ß-cell function in patients with advanced duration of T2DM. Trial registration-Clinicaltrials.gov NCT01759823.

Efficacy of Autologous Bone Marrow-Derived Mesenchymal Stem Cell and Mononuclear Cell Transplantation in Type 2 Diabetes Mellitus: A Randomized, Placebo-Controlled Comparative Study.

Drugs targeting ß-cells have provided new options in the management of T2DM; however, their role in ß-cell regeneration remains elusive. The recent emergence of cell-based therapies such as autologous bone marrow-derived mesenchymal stem cells (ABM-MSCs) and mononuclear cells (ABM-MNCs) seems to offer a pragmatic approach to augment ß-cell function/mass. This study aims to examine the efficacy and safety of ABM-MSC and ABM-MNC transplantation in T2DM and explores alterations in glucose-insulin homeostasis by metabolic studies. Thirty patients of T2DM with duration of disease ≥5 years, receiving triple oral antidiabetic drugs along with insulin (≥0.4 IU/Kg/day) with HbA1c ≤7.5%(≤58.0 mmol/mol), were randomized to receive ABM-MSCs or ABM-MNCs through targeted approach and a sham procedure (n = 10 each). The primary endpoint was a reduction in insulin requirement by ≥50% from baseline, while maintaining HbA1c <7.0% (<53.0 mmol/mol) during 1-year follow-up. Six of 10 (60%) patients in both the ABM-MSC and ABM-MNC groups, but none in the control group, achieved the primary endpoint. At 12 months, there was a significant reduction in insulin requirement in ABM-MSC (P < 0.05) and ABM-MNC groups (P < 0.05), but not in controls (P = 0.447). There was a significant increase in second-phase C-peptide response during hyperglycemic clamp in the ABM-MNC (P < 0.05) group, whereas a significant improvement in insulin sensitivity index (P < 0.05) accompanied with an increase in insulin receptor substrate-1 gene expression was observed in the ABM-MSC group. In conclusion, both ABM-MSCs and ABM-MNCs result in sustained reduction in insulin doses in T2DM. Improvement in insulin sensitivity with MSCs and increase in C-peptide response with MNCs provide newer insights in cell-based therapies.

Daesiho-Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota.

BACKGROUND: Obesity has become a major global health challenge due to its increasing prevalence, and the associated health risk. It is the main cause of various metabolic diseases including diabetes, hypertension, cardiovascular disease, stroke and certain forms of cancer. METHODS AND RESULTS: In the present study we evaluated the anti-obesity property of Daesiho-tang (DSHT), an herbal medicine, using high fat diet (HFD)-induced obese mice as a model. Our results showed that DSHT ameliorated body weight gain, decreased total body fat, regulated expression of leptin and adiponectin genes of adipose tissue and exerted an anti-diabetic effect by attenuating fasting glucose level and serum insulin level in HFD-fed animals. In addition, DSHT-treatment significantly reduced total cholesterol (TC), triglycerides (TG) and increased high density lipoprotein-cholesterol (HDL), glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) levels in serum and reduced deposition of fat droplets in liver. DSHT treatment resulted in significantly increased relative abundance of bacteria including Bacteroidetes, Bacteroidetes/Firmicutes ratio, Akkermansia Bifidobacterium., Lactobacillus, and decreased the level of Firmicutes. Using RT2 profiler PCR array, 39 (46%) genes were found to be differentially expressed in HFD-fed mice compared to normal control. However, normal gene expressions were restored in 36 (92%) genes of HFD-fed mice, when co-exposed to DSHT. CONCLUSION/MAJOR FINDINGS: The results of this study demonstrated that DSHT is an effective herbal formulation in attenuation of obesity in HFD-fed mice through alteration of gene expressions and modulation of intestinal microbiota.

Sinefungin, a natural nucleoside analogue of S-adenosylmethionine, inhibits Streptococcus pneumoniae biofilm growth.

Pneumococcal colonization and disease is often associated with biofilm formation, in which the bacteria exhibit elevated resistance both to antibiotics and to host defense systems, often resulting in infections that are persistent and difficult to treat. We evaluated the effect of sinefungin, a nucleoside analogue of S-adenosylmethionine, on pneumococcal in vitro biofilm formation and in vivo colonization. Sinefungin is bacteriostatic to pneumococci and significantly decreased biofilm growth and inhibited proliferation and structure of actively growing biofilms but did not alter growth or the matrix structure of established biofilms. Sinefungin significantly reduced pneumococcal colonization in rat middle ear. The quorum sensing molecule (autoinducer-2) production was significantly reduced by 92% in sinefungin treated samples. The luxS, pfs, and speE genes were downregulated in biofilms grown in the presence of sinefungin. This study shows that sinefungin inhibits pneumococcal biofilm growth in vitro and colonization in vivo, decreases AI-2 production, and downregulates luxS, pfs, and speE gene expressions. Therefore, the S-adenosylmethionine (SAM) inhibitors could be used as lead compounds for the development of novel antibiofilm agents against pneumococci.

A comparative evaluation of prasugrel and clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

OBJECTIVE: Primary objective of this study was to compare the efficacy of Prasugrel vs. Clopidogrel in the patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) by measuring inhibition of platelet aggregation after loading and maintenance dose of both the drugs. The patients were also assessed for safety of the drugs. METHODS: This was a randomised, double-blind, double-dummy, comparative, multicentric clinical trial in patients with acute coronary syndrome (unstable angina, non-ST elevation MI and ST elevation MI) undergoing PCI. The patients were randomly assigned to receive prasugrel (loading dose of 60 mg followed by maintenance dose of 10-mg once daily) or clopidogrel (loading dose of 300 mg followed by maintenance dose of 75 mg once daily) for a period of 12 weeks. All the patients were co-prescribed aspirin 325 mg with both the drugs. The primary efficacy end point in this study was percentage inhibition of ADP induced platelet aggregation (IPA) at 4 +/- 1 hours after the loading dose and at 30 +/- 3 days during maintenance treatment. The platelet aggregation of both the drugs was measured by whole blood aggregometer using 10 mmol of ADP as an aggregant. Though this study was not powered to see the difference in clinical efficacy parameters, the patients were observed for the incidence of nonfatal MI, nonfatal stroke, re-hospitalization, death, or need for urgent revascularization due to a cardiac ischemic event at days 30 and 90 during the study. The safety of study drugs were evaluated by incidence of major bleeding, reported adverse drug reaction and alterations of any laboratory parameters. RESULT: A total of 220 patients were enrolled at 11 centres across India. Ten patients were given the loading dose of prasugrel or clopidogrel but did not underwent PCI due to change in investigator's decision to go for PCI. Out of 210 eligible patients, 21 patients were discontinued during the study. 157 patients were evaluated for platelet inhibition after loading dose at 4 hours and 150 patients at day 30 during maintenance phase of antiplalelet therapy. The investigators could not perform this test in remaining patients due to urgency and criticality of the patients. 189 patients were observed for the incidence of nonfatal MI, nonfatal stroke, rehospitalisation, urgent revascularisation or death due to a cardiac ischemic event. All eligible patients who received at least a loading dose were evalauted for safety. In prasugrel group, 85 and 77 patients were evaluated for IPA at 4 hours and day 30 respectively whereas in clopdogrel group 72 and 73 patients were tested for IPA at 4 hours and at 30 days. Patients in prasugrel group have demonstrated significantly higher inhibition of platelets as compared to clopidogrel group (82.5% vs 71.1%) at 4 hours and at 30 days (84.1% vs 67.4%). The difference in inhibition of platelets between prasugrel and clopidogrel after loading dose and maintenenace dose was statistically significant (p < or = 0.01). The patients were also evaluated for drug hyporesponsiveness to antiplatelet therapy if IPA was < 20% at day 30 from the baseline. More patients on prasugrel have shown response to antiplatlet therapy than on clopidogrel (97.4% vs 87.6%). The difference between the two groups was statistically significant (p < 0.05). There was no difference observed during the study in the incidence of nonfatal MI, nonfatal stroke, death, rehospitalisation or need for urgent revascularisation due to a cardiac event between prasugrel and clopidogrel. Both the drugs were found to be to be well tolerated and have comparable safety profile. CONCLUSION: This study suggests that prasugrel is more effective than clopidogrel as an anti platelet drug as evident by inhibition of platelet aggregation. More patients on clopidogrel are likely to have poor response to therapy as compared to prasugrel. Both the drugs were well tolerated and have comparable safety profile.

Incidental pneumoparotid detected on computed tomography: Should it raise an alarm?

BACKGROUND: Pneumoparotid is often seen in patients as a result of infection or following maneuvers that lead to increase in intraoral pressures. We describe a short series of 5 cases of incidental pneumoparotid, for the first time, detected during neck contrast-enhanced computed tomography (CECT) examination. METHODS: All neck CECT examinations that had been acquired over a 4-month period for indications other than pertaining to the parotid gland were retrospectively analyzed. RESULTS: Four hundred cases were reviewed. Five of 80 patients in whom CECT was acquired after the "puffed cheek" maneuver were detected to have incidental pneumoparotid. All remained clinically asymptomatic during the examination. CONCLUSIONS: Pneumoparotid may be an incidental finding in patients asked to blow air in a closed mouth during CT/magnetic resonance acquisition. An awareness of this benign finding would prevent sudden alarm of interpreting it as an anaerobic infection of the parotid in such patients.

Dermatofibrosarcoma protuberans with contiguous infiltration of the underlying bone.

Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous neoplasm with pronounced tendency for local recurrence. A case of DFSP that showed direct infiltration into the underlying bone marrow is described. To the best of our knowledge, such direct bony involvement by dermatofibrosarcoma has not been reported in the English literature to date. The role of imaging is also discussed for planning adequate initial treatment, which will result in a lower recurrence rate and improved clinical outcome.