Intravenous ozonized saline therapy as prophylaxis for healthcare workers (HCWs) in a dedicated COVID-19 hospital in India - A retrospective study.

OBJECTIVE: In the current pandemic, Health Care Workers (HCWs) are at a high risk of developing COVID-19. Preventive methods like the use of personal protective equipment, isolation, social distancing, and chemoprophylaxis show limited benefit. Despite standard prophylaxis, many of the HCWs develop COVID-19. Medical ozone therapy has immunomodulatory, antioxidant and antiviral effect, and, therefore, it can be explored as prophylaxis for COVID-19. PATIENTS AND METHODS: We conducted a retrospective controlled cohort study. IV ozonized saline was administered once a day for a total of 4 days in one month in addition to standard prophylaxis for COVID-19 to HCWs in a dedicated COVID hospital. Fresh ozonized saline was prepared for every administration and was given over 1 hour. RESULTS: There were 235 HCWs, 64 received the ozone prophylaxis and 171 did not. The incidence of COVID-19 was significantly (p=0.04) lesser in HCWs that received ozone prophylaxis (4.6%) as compared to those who did not (14.03%). The benefit was seen irrespective of the risk of exposure. In the red zone, 8.69% of the HCWs who received ozone prophylaxis tested positive as opposed to 15.3% of those who did not. In the orange zone, 4.34% of the HCWs who received ozone prophylaxis tested positive, remarkably lesser than those who did not (20%). In the green zone, none of the HCWs who received ozone prophylaxis tested positive; however, 3.4% of the HCWs who did not receive ozone prophylaxis tested positive. No major adverse events were noted. CONCLUSIONS: IV ozonized saline can be used in addition to the standard prophylactic regimen for the prevention of COVID-19 in HCWs. Prospective larger studies are required to establish the potency of IV ozonized saline as prophylaxis.

Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth.

Metastatic competence is contingent upon the aberrant activation of a latent embryonic program, known as the epithelial-mesenchymal transition (EMT), which bestows stem cell properties as well as migratory and invasive capabilities upon differentiated tumor cells. We recently identified the transcription factor FOXC2 as a downstream effector of multiple EMT programs, independent of the EMT-inducing stimulus, and as a key player linking EMT, stem cell traits and metastatic competence in breast cancer. As such, FOXC2 could serve as a potential therapeutic target to attenuate metastasis. However, as FOXC2 is a transcription factor, it is difficult to target by conventional means such as small-molecule inhibitors. Herein, we identify the serine/threonine-specific kinase p38 as a druggable upstream regulator of FOXC2 stability and function that elicits phosphorylation of FOXC2 at serine 367 (S367). Using an orthotopic syngeneic mouse tumor model, we make the striking observation that inhibition of p38-FOXC2 signaling selectively attenuates metastasis without impacting primary tumor growth. In this model, circulating tumor cell numbers are significantly reduced in mice treated with the p38 inhibitor SB203580, relative to vehicle-treated counterparts. Accordingly, genetic or pharmacological inhibition of p38 decreases FOXC2 protein levels, reverts the EMT phenotype and compromises stem cell attributes in vitro. We also identify the EMT-regulator ZEB1-known to directly repress E-cadherin/CDH1-as a downstream target of FOXC2, critically dependent on its activation by p38. Consistent with the notion that activation of the p38-FOXC2 signaling axis represents a critical juncture in the acquisition of metastatic competence, the phosphomimetic FOXC2(S367E) mutant is refractory to p38 inhibition both in vitro and in vivo, whereas the non-phosphorylatable FOXC2(S367A) mutant fails to elicit EMT and upregulate ZEB1. Collectively, our data demonstrate that FOXC2 regulates EMT, stem cell traits, ZEB1 expression and metastasis in a p38-dependent manner, and attest to the potential utility of p38 inhibitors as antimetastatic agents.

Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties.

Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lo stem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lo population of prostate cancer cells with stem-cell properties.

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets.

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated.

Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties.

Emerging evidence suggests that cancers arise in stem/progenitor cells. Yet, the requirements for transformation of these primitive cells remains poorly understood. In this study, we have exploited the 'mammosphere' system that selects for primitive mammary stem/progenitor cells to explore their potential and requirements for transformation. Introduction of Simian Virus 40 Early Region and hTERT into mammosphere-derived cells led to the generation of NBLE, an immortalized mammary epithelial cell line. The NBLEs largely comprised of bi-potent progenitors with long-term self-renewal and multi-lineage differentiation potential. Clonal and karyotype analyses revealed the existence of heterogeneous population within NBLEs with varied proliferation, differentiation and sphere-forming potential. Significantly, injection of NBLEs into immunocompromised mice resulted in the generation of invasive ductal adenocarcinomas. Further, these cells harbored a sub-population of CD44(+)/CD24(-) fraction that alone had sphere- and tumor-initiating potential and resembled the breast cancer stem cell gene signature. Interestingly, prolonged in vitro culturing led to their further enrichment. The NBLE cells also showed increased expression of stemness and epithelial to mesenchymal transition markers, deregulated self-renewal pathways, activated DNA-damage response and cancer-associated chromosomal aberrations-all of which are likely to have contributed to their tumorigenic transformation. Thus, unlike previous in vitro transformation studies that used adherent, more differentiated human mammary epithelial cells our study demonstrates that the mammosphere-derived, less-differentiated cells undergo tumorigenic conversion with only two genetic elements, without requiring oncogenic Ras. Moreover, the striking phenotypic and molecular resemblance of the NBLE-generated tumors with naturally arising breast adenocarcinomas supports the notion of a primitive breast cell as the origin for this subtype of breast cancer. Finally, the NBLEs represent a heterogeneous population of cells with striking plasticity, capable of differentiation, self-renewal and tumorigenicity, thus offering a unique model system to study the molecular mechanisms involved with these processes.

Intimate partner violence: how does it impact major depressive disorder and post traumatic stress disorder among immigrant Latinas?

Intimate Partner Violence (IPV) is prevalent in the general US population, as well as the Latino community. In a cross-sectional study at an immigrant, primary care clinic, we assessed the correlation between IPV history and symptoms of MDD and PTSD in Latino women. We used a structured interview format. Among the 105 women recruited, the 4-week incidence of MDD was 45.7% and the prevalence of PTSD was 19%. Abused women had three times the odds of meeting PTSD criteria than non-abused women. Women meeting PTSD criteria were 10 times likelier to also report MDD. There was no difference in the incidence of MDD among women who reported IPV and those who did not. This study found a correlation of IPV with PTSD, and PTSD with MDD, but not IPV with MDD. Our results indicate a need for mental health interventions in primary care settings for Latina women regardless of IPV history.

Early changes in esophageal motility after endoscopic variceal sclerotherapy or ligation.

INTRODUCTION: Endoscopic variceal sclerotherapy (EVS) and ligation (EVL) are reported to be associated with altered esophageal motility. Most studies have been in patients with alcoholic cirrhosis and ascites. AIMS: To study the early effect of EVS and EVL in patients with portal hypertension without ascites. METHODS: Forty six portal hypertensive patients without ascites underwent esophageal manometry 24 h prior to EVS or EVL and within 24 h of two subsequent sessions. Nineteen such patients but without prior gastrointestinal bleed were studied once as controls. RESULTS: The protocol was completed in 35 patients (cirrhosis--16, noncirrhotic portal hypertension--19; 27 men; mean age 36 years). Basal midexpiratory lower esophageal sphincter pressure was similar in the study group (mean [SD] 20.1 [9.1] mmHg) and controls (17.6 [6.0] mmHg); the pressure did not change following EVS or EVL. Amplitude of contractions in the lower 5 cm of the esophageal body was similar in the two groups (84.8 [43.1] mmHg and 95.9 [59.6] mmHg), and decreased (63.6 [34.0] mmHg; p = 0.03) after two sessions of variceal therapy. The duration of contraction did not change following intervention. Nonperistaltic waves > 2 of 10 swallows were present during the baseline study in 9 patients in each group; 13 and 21 patients (p < 0.02 compared to baseline) developed them after the first and second sessions of therapy, respectively. Percentage of abnormal waves also increased following therapy. Thirteen patients developed esophageal ulcers; there was no correlation between the presence of ulcers and dysmotility. There was no difference in the changes between the EVS and EVL groups, and between patients with cirrhosis and noncirrhotic portal hypertension. CONCLUSION: Both EVS and EVL affect esophageal motility; these changes do not cause significant esophageal symptoms.