Visible-light-mediated radical reactions of indoles with para-quinone methides using eosin Y as an organophotoredox catalyst.

Herein, we demonstrate a redox-neutral, operationally simple, atom-economical, and additive-free approach for the synthesis of indolyl diarylmethanes via a radical reaction of indoles with para-quinone methides (p-QMs) under visible-light mediated reaction conditions using eosin Y as an organophotoredox catalyst. This protocol was found to be compatible with a wide range of differently substituted p-QMs and indoles in organic as well as in aqueous media under visible-light irradiation, furnishing the desired products in good to excellent yields.

Construction of heterocycle-fused tetrahydrocarbazoles through a formal [3 + 3]-annulation of 2-indolylmethanols with para-quinone methides.

A metal-free approach for the synthesis of tetrahydroindolo[2,3-b]carbazoles has been developed through an acid-mediated one-pot [3 + 3]-annulation of 2-indolylmethanols and 3-indolyl-substituted para-quinone methides. This operationally simple protocol allowed us to prepare many unsymmetrical tetrahydroindolo[2,3-b]carbazoles in good to excellent yields with a broad substrate scope. This concept was also elaborated to the synthesis of tetrahydrothieno[2,3-b]carbazoles and tetrahydrothieno[3,2-b]carbazoles.

Acid-catalysed intramolecular Friedel-Crafts annulation of hetero-atom-functionalized para-quinone methides: access to O-, S- and N-based heterocycles.

We describe here an acid-mediated one-pot approach to access substituted xanthene and thioxanthane derivatives from ortho-heteroaryl phenyl-substituted para-quinone methides via 1,6 intramolecular arylation. The scope of this work was further elaborated to the synthesis of 10H-indolo[1,2-a]indole-based heterocyclic systems using indole based para-quinone methides.

Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study.

BACKGROUND: Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. METHODS: RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. RESULTS: Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. CONCLUSIONS: Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.

Surgical outcomes in patients with endoscopic versus transcranial approach for skull base malignancies: a 10-year institutional experience.

OBJECT: The authors performed an extensive comparison between patients treated with open versus an endoscopic approach for skull base malignancy with emphasis on surgical outcomes. METHODS: A single-institution retrospective review of 60 patients who underwent surgery for skull base malignancy between 2009 and 2018 was performed. Disease features, surgical resection, post-operative morbidities, adjuvant treatment, recurrence, and survival rates were compared between 30 patients who received purely open surgery and 30 patients who underwent purely endoscopic resection for a skull base malignancy. RESULTS: Of the 60 patients with skull base malignancy, 30 underwent open resection and 30 underwent endoscopic resection. The most common hisotype for endoscopic resection was squamous cell carcinoma (26.7%), olfactory neuroblastoma (16.7%), and sarcoma (10.0%), and 43.3%, 13.3%, and 10.0% for the open resection cohort, respectively. There were no statistical differences in gross total resection, surgical-associated cranial neuropathy, or ability to achieve negative margins between the groups (p > 0.1, all comparisons). Patients who underwent endoscopic resection had shorter surgeries (320.3 ± 158.5 minutes vs. 495.3 ± 187.6 minutes (p = 0.0003), less intraoperative blood loss (282.2 ± 333.6 ml vs. 696.7 ± 500.2 ml (p < 0.0001), and shorter length of stay (3.5 ± 3.7 days vs. 8.8 ± 6.0 days (p < 0.0001). Additionally, patients treated endoscopically initiated adjuvant radiation treatment more quickly (48.0 ± 20.3 days vs. 72.0 ± 20.5 days (p = 0.01). CONCLUSIONS: An endoscopic endonasal approach facilitates a clinically meaningful improvement in surgical outcomes for skull base malignancies.

De-Escalated Adjuvant Therapy After Transoral Robotic Surgery for Human Papillomavirus-Related Oropharyngeal Carcinoma: The Sinai Robotic Surgery (SIRS) Trial.

BACKGROUND: Treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced-dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression-free survival (PFS) and overall survival while reducing toxicity. METHODS: This study was a nonrandomized phase II trial for early-stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced-dose radiotherapy. Patients with previously untreated p16-positive HPVOPC and <20 pack years' smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50-Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56-Gy chemoradiotherapy with weekly cisplatin). RESULTS: Fifty-four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow-up was 43.9 months (9.6-75.8). Disease-specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan-Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6-59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0-42.7 months); one subject remains alive with disease. CONCLUSION: The results indicate that upfront surgery with neck dissection with reduced-dose radiation for T1-2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de-escalation strategy in HPVOPC. IMPLICATIONS FOR PRACTICE: Transoral robotic surgery can provide a safe platform for de-escalation in carefully selected patients with early-stage human papillomavirus-related oropharyngeal cancer. In this clinical trial, disease-specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged.

Structure of an Unfolding Intermediate of an RRM Domain of ETR-3 Reveals Its Native-like Fold.

Prevalence of one or more partially folded intermediates during protein unfolding with different secondary and ternary conformations has been identified as an integral character of protein unfolding. These transition-state species need to be characterized structurally for elucidation of their folding pathways. We have determined the three-dimensional structure of an intermediate state with increased conformational space sampling under urea-denaturing condition. The protein unfolds completely at 10 M urea but retains residual secondary structural propensities with restricted motion. Here, we describe the native state, observable intermediate state, and unfolded state for ETR-3 RRM-3, which has canonical RRM fold. These observations can shed more light on unfolding events for RRM-containing proteins.

Bis(amino)cyclopropenylidene Catalyzed Rauhut-Currier Reaction between α,ß-Unsaturated Carbonyl Compounds and para-Quinone Methides.

An intermolecular Rauhut-Currier reaction between α,ß-unsaturated carbonyl compounds and p-quinone methides has been developed by employing bis(amino)cyclopropenylidene as a catalyst. This protocol allows access to a variety of vinyl diarylmethane derivatives in moderate to good yields.

A One-Pot Approach to 2,3-Diarylbenzo[ b]furans through N-Heterocyclic Carbene-Catalyzed 1,6-Conjugate Addition Followed by Acid Mediated Dehydrative Annulation.

A one-pot protocol for the synthesis of 2,3-diarylbenzo[ b]furan derivatives through an N-heterocyclic carbene catalyzed 1,6-conjugate addition of aromatic aldehydes to 2-hydroxyphenyl-substituted para-quinone methides followed by acid-mediated dehydrative annulation has been developed. This protocol allowed us to access a wide range of 2,3-diarylbenzo[ b]furan derivatives in moderate to good yields.

Stereotactic Radiosurgery and Immune Checkpoint Inhibitors in the Management of Brain Metastases.

Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive sequelae, and has not been investigated for its immunostimulatory effects. Furthermore, WBRT exposes the entire intracranial tumor immune microenvironment to radiation. SRS delivers a high dose of conformal radiation with image guidance to minimize dose to surrounding normal brain tissue, and appears to promote anti-tumor immunity. In parallel with many of these discoveries, immune checkpoint inhibitors (ICIs) have demonstrated a survival advantage in multiple malignancies commonly associated with brain metastases (e.g., melanoma). Combination SRS and ICI are theorized to be synergistic in anti-tumor immunity directed to brain metastases. The purpose of this review is to explore the synergy of SRS and ICIs, including pre-clinical data, existing clinical data, and ongoing prospective trials.

Subcutaneous Phaeohyphomycosis Caused by Pyrenochaeta romeroi in a Rheumatoid Arthritis Patient: A Case Report with Review of the Literature.

Pyrenochaeta romeroi is a rare fungal agent of chronic, suppurative subcutaneous infections leading to mycetoma. It is an unusual cause of deep, non-mycetomatous infections. We herein present review of the literature along with a case of 61-year-old Indian female with rheumatoid arthritis who developed subcutaneous phaeohyphomycosis caused by Pyrenochaeta romeroi. It posed a diagnostic challenge, as the culture from fine-needle aspirate revealed a non-sporulating dematiaceous mould, which was the only supportive tool for its diagnosis and initiation of the therapy. However, it was the molecular sequencing which played the pivotal role in clinching the final aetiological diagnosis. To the best of our knowledge, this is the 20th case of Pyrenochaeta species infection occurring worldwide and first case report of subcutaneous phaeohyphomycosis caused by Pyrenochaeta romeroi in a rheumatoid arthritis patient.

Supernumerary teeth in Nepalese children.

OBJECTIVE: The objectives of the present study were to investigate the prevalence and characteristics of supernumerary teeth in a patient sample of Nepalese children. STUDY DESIGN: A survey was performed on 2684 patients (1829 females and 1035 males) ranging in age from 6 to 14 for the presence of supernumerary teeth. For each patient with supernumerary teeth the demographic variables (age and sex), number, location, eruption status, and morphology were recorded. Descriptive statistics were performed. RESULTS: Supernumerary teeth were detected in 46 subjects (1.6%), of which 26 were males and 20 were females with a male : female ratio of 1.3 : 1. The most commonly found supernumerary tooth was mesiodens followed by maxillary premolars, maxillary lateral incisor, and mandibular lateral incisor. Of the 55 supernumerary teeth examined, 58.18% (n = 32) had conical morphology, followed by tuberculate (30.90%, n = 17) and supplemental (10.90%, n = 6) forms. The majority of the supernumerary teeth were erupted (56.36%, n = 31). CONCLUSION: The prevalence of supernumerary teeth in Nepalese children was found to be 1.6%, the most frequent type being mesiodens. Conical morphology was found to be the most common form of supernumerary tooth.

Site specific effect of tobacco addiction in upper aerodigestive tract tumors: a retrospective clinicopathological study.

An institutional study was carried out in 102 patients to investigate the site specific effect of addictions, that is, tobacco smoking and tobacco chewing (smokeless), both independently and synergistically in development of malignancies in upper aerodigestive tract through retrograde questionnaire. The histopathologically proven cases were interviewed regarding different forms of addictions followed by clinical examination and investigations for grading (according to Modified Broadmann's method) and TNM staging (according to UICC) according to the tumor site. Statistical analysis was done by Pearson test. Out of all proven cases of cancers, 29.4% were only tobacco chewers (smokeless), 25.5% were only smokers, 42.2% were having both types of tobacco addictions (smoke and smokeless), and only 2.9% were having no addiction. Out of only tobacco chewers (smokeless), 83.3% were of oral cavity cancers, 6.7% were of oro- and hypopharynx and the rest were of others. Among only smokers, 69.2% cases were of laryngeal and oro- and hypopharynx as compared to 11.5% of oral cavity cancers (nearly 6 times). Tobacco (smokeless) chewing is associated with oral cancers whereas tobacco smoking is associated with laryngeal and hypopharyngeal carcinoma. Both smoking and smokeless tobacco act in synergy with each other.

Solitary Pancreatic Metastasis from an Ovarian Carcinoma: A Diagnostic Perplexity.

Ovarian cancer presenting as an isolated pancreatic metastasis after years of treatment is extremely rare. Most such patients are easily misdiagnosed as a case of primary pancreatic cancer. We herein describe a unique case of posttreatment high-grade serous papillary ovarian carcinoma metastasizing to the pancreas that mimicked primary pancreatic cancer and caused a diagnostic dilemma. The approach to such a case, pathogenesis, differential diagnosis, management, and a brief literature review is also presented.

Eosin Y-catalyzed reductive homocoupling of para-quinone methides under visible-light.

In this manuscript, we demonstrate a visible-light driven dimerization of para-quinone methides using eosin Y catalyst via a reductive homocoupling process. This mild and operationally simple methodology was found to be compatible with a variety of differently substituted para-quinone methides and a broad range of tetra-arylethane derivatives were obtained in moderate to good yields (47%-87%).

Variations in anxiety and emotional support among first-year college students across different learning modes (distance and face-to-face) during COVID-19.

College students with more emotional support experience lower levels of anxiety and other psychosocial and behavioral problems. During the COVID-19 pandemic, the emotional well-being of college students was additionally challenged by an abrupt shift to distance learning followed by a return to face-to-face classes. In this exploratory study, we compared the levels of perceived emotional support and anxiety among incoming first-year undergraduate students, prior to starting classes, which included different learning modes in five semesters of instruction from 2021-2023 (three distance semesters and two face-to-face semesters). Data from 8659 undergraduate students were extracted from a Mexican state university database, corresponding to students' responses collected during new student orientation week. Participants were students in the arts and humanities (9.7%), social and legal sciences (38%), life and health sciences (28.9%), and engineering and architecture (23.4%). Anxiety levels were measured with the GAD-7 scale, and emotional support was measured using a subscale of the PERACT-R (To go through with resilience) inventory. Comparisons of emotional support and anxiety scores among semesters revealed highly significant differences with small effect sizes. Anxiety levels increased significantly with mean average of 6.65 SD(5.52) during the baseline measure to the highest in 2022-2 to 7.53 SD(5.3) and Emotional Support decreased systematically each semester from baseline mean = 8.03 SD(2.0) to the lowest 7.52 SD(1.8) in 2022-2. The results show that a return to face-to-face classes was associated with increased anxiety levels, whereas levels of emotional support systematically decreased across the five semesters. MANOVA analysis revealed significant differences in anxiety and emotional support scores between semesters, with peaks during the learning mode semester that students returned to face-to-face classes after distance learning even after adjusting for gender. Given that the effect of emotional support on anxiety may be related to success in future educational and professional activities, it is important to develop interventions to restore and increase college students' emotional support levels and develop anxiety management strategies.

Fevogrit, a polyherbal medicine, mitigates endotoxin (lipopolysaccharide)-induced fever in Wistar rats by regulating pro-inflammatory cytokine levels.

BACKGROUND: Fever is characterized by an upregulation of the thermoregulatory set-point after the body encounters any pathological challenge. It is accompanied by uncomfortable sickness behaviors and may be harmful in patients with other comorbidities. We have explored the impact of an Ayurvedic medicine, Fevogrit, in an endotoxin (lipopolysaccharide)-induced fever model in Wistar rats. METHODS: Active phytoconstituents of Fevogrit were identified and quantified using ultra-high-performance liquid chromatography (UHPLC) platform. For the in-vivo study, fever was induced in male Wistar rats by the intraperitoneal administration of lipopolysaccharide (LPS), obtained from Escherichia coli. The animals were allocated to normal control, disease control, Paracetamol treated and Fevogrit treated groups. The rectal temperature of animals was recorded at different time points using a digital thermometer. At the 6-h time point, levels of TNF-α, IL-1ß and IL-6 cytokines were analyzed in serum. Additionally, the mRNA expression of these cytokines was determined in hypothalamus, 24 h post-LPS administration. RESULTS: UHPLC analysis of Fevogrit revealed the presence of picroside I, picroside II, vanillic acid, cinnamic acid, magnoflorine and cordifolioside A, as bioactive constituents with known anti-inflammatory properties. Fevogrit treatment efficiently reduces the LPS-induced rise in the rectal temperature of animals. The levels and gene expression of TNF-α, IL-1ß and IL-6 in serum and hypothalamus, respectively, was also significantly reduced by Fevogrit treatment. CONCLUSION: The findings of the study demonstrated that Fevogrit can suppress LPS-induced fever by inhibiting peripheral or central inflammatory signaling pathways and could well be a viable treatment for infection-induced increase in body temperatures.

Optimization of wet granulation process for manufacturing Rivaroxban generic immediate-release tablets using PBPK modeling and simulations.

Granulation is the critical process for the pharmaceutical development of poorly water-soluble drug products. Poorly formulated products have challenges in dissolution and bioequivalence studies. Rivaroxaban (RXB) is a poorly soluble drug and has 66% fasting bioavailability at a high strength of 20 mg. Establishing the bioequivalence between test and reference products for high strength requires comparative dissolution profiles and bioequivalence. Improper granulation products and the rest of the batches failed in virtual bioequivalence. The present study provided insight into the optimization of the wet granulation process for manufacturing RXB generic immediate-release tablets using PBPK modeling and simulations. Furthermore, PBPK models are not only useful for formulation optimization but also for process optimization during pharmaceutical product development. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00249-6.

Head and Neck Cancer Patient Population, Management, and Oncologic Outcomes from the COVID-19 Pandemic.

The COVID-19 pandemic precipitated drastic changes in cancer care. Its impact on the U.S. head and neck cancer population has yet to be fully understood. This study aims to understand the impact of pandemic-related changes on the head and neck cancer population. An observational study of head and neck cancer patients at a single institution during the spring of 2020 and 2019 was performed. Clinical characteristics and survival outcomes were analyzed. In 2020, 54 head and neck cancer patients were evaluated in the department of radiation oncology vs. 74 patients seen in 2019; 42% of the patients were female in 2019 versus 24% in 2020 (p = 0.036). The median follow-up time was 19.4 and 31 months for 2020 and 2019, respectively. After adjusting for stage, the relapse-free survival probability at 6 and 12 months was 79% and 69% in 2020 vs. 96% and 89% in 2019, respectively (p = 0.036). There was no significant difference in the overall survival, with 94% and 89% in 2020 and 2019, respectively (p = 0.61). Twenty-one percent of patients received induction chemotherapy in 2020 versus 5% in 2019 (p = 0.011); significantly more treatment incompletions occurred in 2020, 9% vs. 0% in 2019 (p = 0.012). Moreover, the stage-adjusted RFS differed between cohorts, suggesting head and neck cancer patients seen during the initial wave of COVID-19 may experience worse oncologic outcomes.