RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells.

Objectives: Mono(ADP-ribosyl)ation (MARylation), a post translational modification of proteins, is emerging as an important regulator of the biology of cancer cells. PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART), MARylates its substrate α-tubulin in ovarian cancer cells, promoting destabilization of microtubules, cell growth, and migration. Recent development of RBN-2397, a potent inhibitor that selectively acts on PARP7, has provided a new tool for exploring the role of PARP7 catalytic activity in biological processes. In this study, we investigated the role of PARP7 catalytic activity in the regulation of ovarian cancer cell biology via MARylation of α-tubulin. Methods: Ovarian cancer cell lines (OVCAR4, OVCAR3) were treated with RBN-2397 and paclitaxel, both separately and in combination. Western blotting and immunoprecipitation confirmed the effects of RBN-2397 on α-tubulin MARylation and stabilization. Cell proliferation and migration were assessed, and α-tubulin stabilization was quantified using immunofluorescent imaging. RNA-sequencing was performed to assess the effects on gene expression changes. Results: RBN-2397 inhibited PARP7 activity, decreasing α-tubulin MARylation, leading to its stabilization, and reducing cancer cell proliferation and migration. The addition of paclitaxel further enhanced these effects, highlighting a synergistic interaction between the two drugs. Mutating the site of PARP7-mediated MARylation on α-tubulin similarly resulted in microtubule stabilization and decreased cell migration in the presence of paclitaxel. Conclusions: This study demonstrates that targeting PARP7 with RBN-2397, particularly in combination with paclitaxel, offers an effective strategy for inhibiting aggressive ovarian cancer cell phenotypes. Our findings underscore the potential of combining PARP7 inhibitors with established chemotherapeutics to enhance treatment efficacy in ovarian cancer.

Waste bamboo-derived magnetically separable bamboo-activated carbon: from characterization to effective remediation of fluoride (F-) ions from water.

An effective and affordable nanoadsorbent, magnetically separable magnetite-activated bamboo carbon (MABC), was obtained from waste bamboo biomass via pyrolysis of bamboo chunks and the co-precipitation method using ferrous and ferric chloride as iron precursors. The synthesized nanosorbents were characterised using XRD, SEM, and DLS techniques to study the surface characteristics and morphology. Chemical composition, optical absorption, and magnetic properties were studied using FTIR spectroscopy, UV-vis spectroscopy, and VSM, respectively. The BET surface area, porosity and surface charge were determined using N2 adsorption-desorption isotherm and zeta potential technique. The cytotoxicity and antimicrobial properties of BC, ABC and MABC were investigated against prokaryotes and eukaryotes. The result demonstrates the nontoxic nature of BC, ABC and MABC, indicating their significant potential for addressing water treatment using sustainable and eco-friendly nanosorbents. Comparative fluoride ion removal studies were performed using ABC and MABC NPs. About 99.6% of F- ions were adsorbed using MABC and 75.9% were adsorbed using ABC. Thus, MABC NPs were used as sorbents for the rest of the fluoride ion adsorption parameters. The batch fluoride ion sorption was performed at various sorption parameters, such as diverse solution pH (1.0-8.0), temperature (25-45 °C), agitation times (10-60 min), and adsorbent dose (0.01-0.04 g L-1). The pseudo-second-order kinetic model exhibited the best fit with F- ion adsorption (95.96 mg g-1) compared with the pseudo-first-order model (12.30 mg g-1), thereby indicating chemisorption adsorption. The exhausted MABC was recovered from the aqueous solution using a bar magnet. Regeneration studies of exhausted MABC were successfully performed using NaOH (0.1 M) as a desorbing agent.

Predicting VTE and utility of thromboprophylaxis in metastatic and recurrent cervical cancer.

OBJECTIVE: Patients with cervical cancer who are diagnosed with venous thromboembolism (VTE) have worse outcomes compared to those not affected. There has yet to be a reliable method to predict or prevent VTE in cervical cancer patients. Our objective is to describe the incidence of VTE in patients with recurrent and metastatic (r/mCC) and determine risk factors that may predict VTE in this setting. METHODS: We performed an observational cohort study of 386 patients with r/mCC who received at least one line of systemic chemotherapy. We collected demographic, clinical, histologic data and Khorana scores for all patients. Inclusion and exclusion criteria were applied before analysis. Statistical analysis was performed using Pearson chi-square, Student's t-test, and Wilcoxon rank-sum. RESULTS: 232 patients were included for evaluation. Mean age was 49 years (range 20-83). The majority (167, 72%) of patients had squamous cell histology. 169 (72.8%) patients received treatment for recurrent disease and 63 (27.2%) for metastatic, stage IVB disease. 180 (78%) patients received prior radiation and 134 (58%) received bevacizumab. VTE was diagnosed in 89 (38%) patients. There were no statistically significant differences amongst clinical and pathologic characteristics between patients who developed VTE and those who did not. There was no significant association between BMI, Khorana score, radiation, bevacizumab, or immunotherapy and the development of VTE. CONCLUSION: Approximately 40% of patients with r/mCC experienced a new VTE. There were no independent risk factors that could predict VTE in this population. Due to the overwhelmingly high incidence of VTE, prophylactic anticoagulation could be strongly considered in patients with r/mCC.

Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

Cytokine profile, neutralisation potential and viral replication dynamics in sera of chikungunya patients in India: a cross-sectional study.

Background: Chikungunya disease (CHIKD) is a threat to global health, as it impairs the quality of life of an infected individual ranging from months to years. A systematic evaluation of the serological, virological, and immunological aspects of the circulating viruses and their impact on the host response is imperative for better understanding of the evolving disease dynamics. Methods: Serum samples were collected from 196 acute CHIKD patients from ten tertiary care hospitals across India during 2016-2021. Out of 196 patients, paired convalescent samples were collected from 51 patients (one-month post-onset of symptoms). The serum samples were profiled for cytokines and neutralisation capacity. Further, chikungunya virus (CHIKV) was isolated from the acute sera and the replication kinetics of the clinical isolates was evaluated. Findings: Serological analysis indicated that neutralisation could be correlated to seroconversion in the convalescent phase but not found significant in acute phase. In the acute phase samples, there was a correlation between elevated serum levels of IFN-γ, IP-10, MCP-1 and MIG and disease severity. During convalescent phase, pro-inflammatory markers such as IL-6, IL-1ß, IL-9 and IP-10 were found to be elevated with a corresponding decline in the secretion of anti-inflammatory cytokines such as IL-4 and IL-10, which correlated with persistent arthralgia. Analysis of replication of the clinical isolates revealed that 68.4% of viruses were fast-growing in the Vero cells (cytopathic effect [CPE] observed within 24 h post-infection), and their corresponding acute serum samples showed an elevated secretion of IFN-α, IL-1RA, IL-17F, IL-9, MCP-1 and MIP-1α. Interpretation: This study provides an important overview of neutralisation capabilities and cytokine responses along with virus pathogenesis associated with CHIKV infections in India. Funding: Biotechnology Industry Research Assistance Council (BIRAC).

Molecular insights of anti-diabetic compounds and its hyaluronic acid conjugates against aldose reductase enzyme through molecular modeling and simulations study-a novel treatment option for inflammatory diabetes.

CONTEXT: Chronic inflammation is a risk factor for diabetes, but it can also be a complication of diabetes, leading to severe diabetes and causing many other clinical manifestations. Inflammation is a major emerging complication in both type I and type II diabetes, which causes increasing interest in targeting inflammation to improve and control diabetes. Diabetes with insulin resistance and impaired glucose utilization in humans and their underlying mechanism is not fully understood. But a growing understanding of the intricacy of the insulin signaling cascade in diabetic inflammatory cells reveals potential target genes and their proteins responsible for severe insulin resistance. With this baseline concept, the current project explores the binding affinities of the hyaluronic acid anti-diabetic compounds conjugates to such target proteins in diabetic inflammatory cells and their molecular geometries. A range of 48 anti-diabetic compounds was screened against aldose reductase binding pocket 3 protein target through in silico molecular docking, and results revealed that three compounds viz, metformin (CID:4091), phenformin (CID:8249), sitagliptin (CID:4,369,359), possess significant binding affinity out of 48 chosen drugs. Further, these three anti-diabetic compounds were conjugated with hyaluronic acid (HA), and their binding affinity and their molecular geometrics towards aldose reductase enzyme were screened compared with the free form of the drug. The molecular geometries of three shortlisted drugs (metformin, phenformin, sitagliptin) and their HA conjugates were also explored through density functional theory studies, and it proves their good molecular geometry towards pocket 3 of aldose reductase target. Further, MD simulation trajectories affirm that HA conjugates possess good binding affinity and simulation trajectories with protein target aldose reductase than a free form of the drug. Our current study unravels the new mechanism of drug targeting for diabetes through HA conjugation for inflammatory diabetes. HA conjugates act as novel drug candidates for treating inflammatory diabetes; however, it needs further human clinical trials. METHODS: For ligand structure, PubChem, ACD chem sketch, and online structure file generator platform are utilized for ligand preparation. Target protein aldose reductase obtained from protein database (PDB). For molecular docking analysis, AutoDock Vina (Version 4) was utilized. pKCSM online server used to predict ADMET properties of the above three shortlisted drugs from the docking study. Using mol-inspiration software (version 2011.06), three shortlisted compounds' bioactivity scores were predicted. DFT analysis for three shortlisted anti-diabetic drugs and their hyaluronic acid conjugates were calculated using a functional B3LYP set of Gaussian 09 software. Molecular dynamics simulation calculations for six chosen protein-ligand complexes were done through YASARA dynamics software and AMBER14 force field.

Comparative anti-Diabetic potential of phytocompounds from Dr. Duke's phytochemical and ethnobotanical database and standard antidiabetic drugs against diabetes hyperglycemic target proteins: an in silico validation.

In the current investigation, the antidiabetic potential of 40 phytocompounds from Dr. Dukes phytochemical and ethanobotanical database and three antidiabetic pharmaceuticals from the market comparatively validated against hyperglycemic target proteins. Silymarin, proanthocyanidins, merremoside, rutin, mangiferin-7-O-beta-glucoside, and gymnemic acid exhibited good binding affinity toward protein targets of diabetes among the 40 phytocompounds from Dr.Dukes database over three chosen antidiabetic pharmaceutical compounds. Further these phytocompounds and sitagliptin are validated for its ADMET and bioactivity score to screen its pharmacological and pharmacokinetics properties. Silymarin, proanthocyanidins, rutin along with sitagliptin screened for DFT analysis found that phytocompounds have great Homo-Lumo orbital energies over commercial pharmaceutical sitagliptin. Finally, four complexes of alpha amylase-silymarin, alpha amylase-sitagliptin, aldose reductase-proanthocyanidins, and aldose reductase-sitagliptin screened for MD simulation and MMGBSA analysis, results shown that the phytocompounds silymarin and proanthocyanidins have strong affinities for binding to the binding pockets of alpha amylase and aldose reductase respectively over antidiabetic pharmaceuticals. Our current study proven proanthocyanidins and silymarin act as novel antidiabetic compounds toward diabetic target protein but it require clinical trial to evaluate its clinical pertinence toward diabetic target proteins.Communicated by Ramaswamy Sarma.

Risk factors for catheter-associated urinary tract infections following radical hysterectomy for cervical cancer.

BACKGROUND: Radical hysterectomy is the mainstay of treatment for early-stage cervical cancer. Urinary tract dysfunction is one of the most common complications after radical hysterectomy, and prolonged catheterization has previously been defined as a significant risk factor for catheter-associated urinary tract infections. OBJECTIVE: This study aimed to determine the rate of catheter-associated urinary tract infections after radical hysterectomy for cervical cancer, and to identify additional risk factors for developing catheter-associated urinary tract infections in this population. STUDY DESIGN: We reviewed patients who underwent radical hysterectomy for cervical cancer from 2004 to 2020 after institutional review board approval. All patients were identified from institutional Gynecologic Oncology surgical and tumor databases. The inclusion criterion was radical hysterectomy for early-stage cervical cancer. Exclusion criteria included inadequate hospital follow-up, insufficient records of catheter use in the electronic medical record, urinary tract injury, and preoperative chemoradiation. Catheter-associated urinary tract infection was defined as an infection diagnosed in a catheterized patient or within 48 hours of catheter removal, with significant bacteriuria (>103 cfu/mL) and symptoms or signs attributable to the urinary tract. Data analysis was performed using comparative analysis and univariate and multivariable logistic regression using Excel, GraphPad Prism, and IBM SPSS Statistics. RESULTS: Of the 160 included patients, 12.5% developed catheter-associated urinary tract infections. In univariate analysis, catheter-associated urinary tract infection was significantly associated with current smoking history (odds ratio, 3.76; 95% confidence interval, 1.39-10.08), minimally invasive surgical approach (odds ratio, 5.24; 95% confidence interval, 1.91-16.87), estimated surgical blood loss >500 mL (odds ratio, 0.18; 95% confidence interval, 0.04-0.57), operative time >300 minutes (odds ratio, 2.92; 95% confidence interval, 1.07-9.36), and increased duration of catheterization (odds ratio, 18.46; 95% confidence interval, 3.67-336). After adjusting for interactions and controlling for potential confounders with multivariable analysis, current smoking history and catheterization for >7 days were identified as independent risk factors for development of catheter-associated urinary tract infections (adjusted odds ratio, 3.94; 95% confidence interval, 1.28-12.37; adjusted odds ratio, 19.49; 95% confidence interval, 2.78-427). CONCLUSION: Preoperative smoking cessation interventions for current smokers should be implemented to decrease risk for postoperative complications, including catheter-associated urinary tract infections. In addition, catheter removal within 7 postoperative days should be encouraged in all women undergoing radical hysterectomy for early-stage cervical cancer in an effort to decrease infection risk.

Isolated para-aortic nodal recurrence after treatment of early stage cervical carcinoma.

OBJECTIVE: Surgical evaluation of lymph node metastasis is paramount in the treatment of cervical cancer. We sought to explore the outcomes of patients with and without para-aortic lymphadenectomy undergoing curative-intent radical hysterectomy for stage IA-IIA cervical cancer. METHODS: Institutional data were retrospectively reviewed to identify women undergoing curative-intent radical hysterectomy with concurrent lymphadenectomy for stage IA-IIA cervical carcinoma from 2004 to 2021. Any carcinoma histology was allowed. Clinical risk stratification was performed according to GOG 92 and GOG 109 protocols. Disease outcomes, patterns of recurrence, and survival were analyzed with Chi square, t-test, Kaplan-Meier, and Cox proportional hazards multivariable statistics. RESULTS: 300 patients were identified, 265 met inclusion criteria. Median follow up was 56 months. Pelvic lymphadenectomy (PLND) was performed in 71%, with the remainder undergoing combined para-aortic dissection (PPaLND). Baseline patient demographics and presence of clinical risk factors were well balanced between groups. PPaLND was more common in patients undergoing open surgery (OR 10.58, p <.0001), and tumors were larger in this group (2.96 vs 2.12 cm, p = .0002) and more likely non-squamous histology (OR 2.02, p = .017). Recurrence of disease was present in 13% of cases, with no difference between PLND and PPaLND regardless of histology. There were zero cases of isolated PaLN recurrence in either group. Neither progression free nor overall survival was different between groups. Prophylactic extended field radiation (EFRT) was not prescribed. CONCLUSION: Omission of PaLN dissection, in the absence of suspicious nodes, did not decrease survival. There were no isolated PaLN recurrences after PLND alone.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

SARS-CoV-2 severity classification from plasma sample using confocal Raman spectroscopy.

The world is on the brink of facing coronavirus's (COVID-19) fourth wave as the mutant forms of viruses are escaping neutralizing antibodies in spite of being vaccinated. As we have already witnessed that it has encumbered our health system, with hospitals swamped with infected patients observed during the viral outbreak. Rapid triage of patients infected with SARS-CoV-2 is required during hospitalization to prioritize and provide the best point of care. Traditional diagnostics techniques such as RT-PCR and clinical parameters such as symptoms, comorbidities, sex and age are not enough to identify the severity of patients. Here, we investigated the potential of confocal Raman microspectroscopy as a powerful tool to generate an expeditious blood-based test for the classification of COVID-19 disease severity using 65 patients plasma samples from cohorts infected with SARS-CoV-2. We designed an easy manageable blood test where we used a small volume (8 µl) of inactivated whole plasma samples from infected patients without any extra solvent usage in plasma processing. Raman spectra of plasma samples were acquired and multivariate exploratory analysis PC-LDA (principal component based linear discriminant analysis) was used to build a model, which segregated the severe from the non-severe COVID-19 group with a sensitivity of 83.87%, specificity of 70.60% and classification efficiency of 76.92%. Among the bands expressed in both the cohorts, the study led to the identification of Raman fingerprint regions corresponding to lipids (1661, 1742), proteins amide I and amide III (1555, 1247), proteins (Phe) (1006, 1034), and nucleic acids (760) to be differentially expressed in severe COVID-19 patient's samples. In summary, the current study exhibits the potential of confocal Raman to generate simple, rapid, and less expensive blood tests to triage the severity of patients infected with SARS-CoV-2.

Docetaxel treatment for widely metastatic invasive vulvar extramammary Paget's disease with multifocal bone metastasis.

•Invasive extramammary Paget's disease of the vulva is rare.•Distant metastasis has a very poor prognosis.•Given rarity of disease, no standardized treatment exists.•Single agent docetaxel is a viable treatment for metastatic invasive extramammary Paget's disease.

Clostridium and Bacteroides bacteremia as initial presentation of uterine carcinosarcoma.

•Anaerobic bacteremia with gynecologic pathology can lead to rapid deterioration.•Frequent physical examination and bedside assessment are critical in management.•Surgical intervention is often necessary for Clostridium and Bacteroides infection.

Shimon Vega in the eyes of his students and postdocs.

Professor Shimon Vega (1943-2021) of the Weizmann Institute of Science passed away on the 16-th of November. Shimon Vega established theoretical frameworks to develop and explain solid-state nuclear magnetic resonance (NMR) and dynamic nuclear polarization (DNP) techniques and methodologies. His departure left a profound mark on his many students, postdocs, and colleagues. Shortly after his passing, we all assembled spontaneously for an international online meeting to share our reflections and memories of our experiences in Shimon's lab and how they affected us deeply during that period of timeand throughout our scientific careers. These thoughts and feelings were put here into writing.

Combinatorial Treatment with PARP-1 Inhibitors and Cisplatin Attenuates Cervical Cancer Growth through Fos-Driven Changes in Gene Expression.

Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate the growth of cells representing cervical adenocarcinoma and cervical squamous cell carcinoma. Moreover, a combination of PARPi with cisplatin increased cisplatin-mediated cytotoxicity in cervical cancer cells. This was accompanied by a dramatic alteration of the transcriptome. The FOS gene, which encodes the transcription factor Fos, was one of the most highly upregulated genes in the dual treatment condition, leading to increased Fos protein levels, greater Fos binding to chromatin, and the subsequent induction of Fos target genes. Increased expression of Fos was sufficient to hinder cervical cancer growth, as shown by ectopic expression of Fos in cervical cancer cells. Conversely, Fos knockdown enhanced cell growth. Collectively, these results indicate that by inducing FOS expression, PARPi treatment in combination with cisplatin leads to inhibition of cervical cancer proliferation, likely through a Fos-specific gene expression program. IMPLICATIONS: Our observations, which link the gene regulatory effects of PARPi + cisplatin to the growth inhibitory effects of FOS expression in cervical cancer cells, strengthen the rationale for using PARPi with cisplatin as a therapy for cervical cancer.

COVID-19 Serological Survey-3 Prior to Second Wave in Mumbai, India.

Background: Subsequent to serosurveys 1 and 2 for COVID-19 carried out in three wards of Mumbai in July and August 2020, Municipal Corporation of Greater Mumbai conducted serosurvey 3 in March 2021. This was to identify the extent of exposure by testing specific IgG antibodies against COVID-19. Material and Methods: A cross-sectional study was conducted to find the prevalence of seropositivity in Mumbai, which included 10,197 samples belonging to patients visiting public dispensaries (slum population, 6006) and private (nonslum population, 4191) laboratories of Aapli Chikitsa network for blood investigations for non-COVID illnesses. The ward-wise number of unlinked anonymous samples from 24 wards was predecided by using probability proportionate sampling. The samples were collected using quota sampling technique as per predecided sample for each ward. These samples collected from nonimmunized individuals were tested for IgG antibodies at the Molecular Biology Laboratory of Kasturba Hospital for Infectious Diseases by chemiluminescence assay (CLIA) method. Results: The overall seropositivity was found to be 36.3% (41.6% in slum and 28.59% in nonslum population). It was more in city wards (38.28%) followed by western suburb (36.47%) and then eastern suburb wards (34.86%), matching with the proportion of cases in these wards during the study period. There was no significant difference in seropositivity among males and females and in different age groups. Conclusions: Seropositivity is higher in slum areas than nonslum areas. It has reduced in slum areas and increased in nonslum areas as compared to findings of serosurveys 1 and 2. This explains the detection of a greater number of cases from nonslum areas in the second wave. The average seropositivity of 36.3% justifies the necessity of immunization on a wider scale in the city. Periodic serosurveys are required at fixed intervals to monitor the trend of infection and level of herd immunity.

Immune profile and responses of a novel dengue DNA vaccine encoding an EDIII-NS1 consensus design based on Indo-African sequences.

The ongoing COVID-19 pandemic highlights the need to tackle viral variants, expand the number of antigens, and assess diverse delivery systems for vaccines against emerging viruses. In the present study, a DNA vaccine candidate was generated by combining in tandem envelope protein domain III (EDIII) of dengue virus serotypes 1-4 and a dengue virus (DENV)-2 non-structural protein 1 (NS1) protein-coding region. Each domain was designed as a serotype-specific consensus coding sequence derived from different genotypes based on the whole genome sequencing of clinical isolates in India and complemented with data from Africa. This sequence was further optimized for protein expression. In silico structural analysis of the EDIII consensus sequence revealed that epitopes are structurally conserved and immunogenic. The vaccination of mice with this construct induced pan-serotype neutralizing antibodies and antigen-specific T cell responses. Assaying intracellular interferon (IFN)-γ staining, immunoglobulin IgG2(a/c)/IgG1 ratios, and immune gene profiling suggests a strong Th1-dominant immune response. Finally, the passive transfer of immune sera protected AG129 mice challenged with a virulent, non-mouse-adapted DENV-2 strain. Our findings collectively suggest an alternative strategy for dengue vaccine design by offering a novel vaccine candidate with a possible broad-spectrum protection and a successful clinical translation either as a stand alone or in a mix and match strategy.

Does Prophylactic Paraortic Lymph Node Irradiation Improve Outcomes in Women With Stage IIIC1 Endometrial Carcinoma?

PURPOSE: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC). METHODS AND MATERIALS: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes. RESULTS: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79). CONCLUSIONS: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.

Human Papillomavirus‒Positive and ‒Negative Vulvar Squamous Cell Carcinoma Are Biologically but Not Clinically Distinct.

Vulvar squamous cell carcinoma pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remain ambiguous across studies. In this study, we present a retrospective cohort analysis of 36 patients with invasive vulvar squamous cell carcinoma where HPV status was determined using RNA in situ hybridization and PCR. Clinical annotation, p16 immunohistochemistry, PD-L1 immunohistochemistry, HPV16 circular E7 RNA detection, and RNA sequencing of the cases were performed. A combination of in situ hybridization and PCR identified 20 cases (55.6%) as HPV positive. HPV status did not impact overall survival (hazard ratio: 1.36, 95% confidence interval = 0.307-6.037, P = 0.6857) or progression-free survival (hazard ratio: 1.12, 95% confidence interval = 0.388-3.22, P = 0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n = 23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs, including several circular RNAs that have previously been implicated in the pathogenesis of other cancers.