Efficacy of Cemiplimab as Adjuvant or Neoadjuvant Therapy in the Treatment of Cutaneous Squamous Cell Carcinoma.

INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the White population. Unfortunately, the prognosis of advanced cSCC is poor, and management can be challenging. Until recently, the choice of systemic medications was limited, and those that were available had modest efficacy. Cemiplimab is an anti-programmed cell-death protein 1 inhibitor and the first immunotherapeutic agent approved for the treatment of metastatic or locally advanced cSCC. The purpose of this study was to evaluate the efficacy of cemiplimab when used as adjuvant or neoadjuvant therapy in patients treated at our institution. METHODS: A retrospective review of patients with locally advanced or metastatic cSCC who were treated with cemiplimab as adjuvant or neoadjuvant therapy at a single institution between February 2019 and November 2022 was performed. Response to treatment was objectively assessed based on Response Evaluation Criteria in Solid Tumors, version 1.1, criteria. The primary end point was objective response rate. Secondary endpoints included time to observed response, disease-control rate, progression-free survival, overall survival, and adverse effects of therapy. RESULTS: A total of 6 patients were identified with a median age of 79 years (range, 51-90 years). Four patients had locally advanced cSCC, and 2 had distant metastasis. Cemiplimab was used as adjuvant therapy in 3 patients and neoadjuvant therapy in 2 patients. There was 1 patient in which it was used for limb salvage, who would have otherwise required an amputation. Objective response rate, complete response, and partial response were 66% (4 of 6), 33% (2 of 6), and 33% (2 pf 6), respectively. Average time to observed response was 2.9 months. Disease-control rate was 83% (5 of 6), and average progression-free survival was 10 months. Toxicity was reported in 2 patients, both of which were grade 1 severity. CONCLUSIONS: Cemiplimab has established its utility in the treatment of advanced cSCC, demonstrating clinical efficacy while generally having a tolerable adverse effect profile. Our preliminary results suggest that cemiplimab has potential as an adjuvant or neoadjuvant therapy in combination with surgery for treatment of cSCC.

Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine.

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.

A Case Study of Furunculosis following an Ayurvedic Oil Massage, Sudation Therapy, and Lessons to Learn.

India has a long history of using sudation therapy and oil massage as Ayurvedic treatments. However, nothing is known about its side effects, and just two studies have identified side effects as cutaneous adverse drug reactions brought on by Ayurvedic oil massage. We are presenting the example of a 72-year-old adult man who visited our hospital and had his right knee massaged with Nirgudi oil followed by sudation therapy. Erythema, papules, itchiness, and scorching pain were some of his symptoms. However, these sensations only partially abated once we quit sudation therapy. Our investigation demonstrates that a Nirgudi oil massage or sudation causes the skin reaction associated with furunculosis. This case report illustrates the necessity of being aware of Panchakarma-related consequences and suggests that medical practitioners, patients, and product makers take into account the likelihood of such a reaction following Nirgudi oil massage and sudation therapy as a precaution.

Rare Presentation of Primary Classical Hodgkin Lymphoma of a Rectosigmoid Colon in a 79-Year-Old With a History of Irritable Bowel Syndrome.

We discuss the case of a 79-year-old immunocompetent male who presented with weight loss and diarrhea and ultimately was found to have a rectosigmoid mass on a colonoscopy. Even though initial biopsies obtained during colonoscopy were non-diagnostic, considering the likelihood of malignancy, lower anterior resection was performed, and pathology confirmed the diagnosis of primary Hodgkin's lymphoma of the sigmoid colon. Hodgkin's lymphoma typically presents as painless supra-diaphragmatic lymphadenopathy with B symptoms such as fever, unexplained weight loss, and drenching night sweats. Due to the rarity of primary Hodgkin lymphoma in the colon and its non-specific initial presentation, we believe sharing this case will bring awareness to the atypical presentation of Hodgkin lymphomas.

Effectiveness of smoking cessation interventions among persons with cancer: A systematic review.

OBJECTIVES: Continued smoking after cancer diagnosis is associated with worse outcomes, however, many persons diagnosed with cancer who smoke are unable to quit successfully. Effective interventions are needed to promote quitting in this population. The purpose of this systematic review is to understand the most effective interventions for smoking cessation among persons with cancer and to identify gaps in knowledge and methodology to suggest directions for future research. METHODS: Three electronic databases (The Cochrane Central Register of Controlled trials, MEDLINE, and EMBASE) were searched for studies of smoking cessation interventions among persons with cancer, published up to 1 July 2021. Title and abstract screening, full-text review, and data extraction was completed by two independent reviewers, via Covalence software, with any discordance resolved by a third reviewer. A quality assessment was completed using the Cochrane Risk of Bias Tool Version 2. RESULTS: Thirty-six articles were included in the review, including 17 randomized-controlled trials (RCTs) and 19 non-RCT studies. Of the 36 studies, 28 (77.8%) utilized an intervention that included both counseling and medication, with 24 (85.7%) providing medication to participants at no cost. Abstinence rates in the RCT intervention groups (n = 17) ranged from 5.2% to 75%, while the non-RCTs found abstinence rates ranging from 15% to 46%. Overall, studies met a mean of 2.28 out of seven quality items, ranging from 0 to 6. CONCLUSIONS: Our study highlights the importance of utilizing intensive combined behavioral and pharmacological interventions for persons with cancer. While combined therapy interventions seem to be the most effective, more research is needed, as current studies have several quality issues, including the lack of biochemical verification for abstinence.

Symptomatic versus asymptomatic primary hyperparathyroidism: A systematic review and meta-analysis.

Purpose: Primary hyperparathyroidism (PHPT) is the underlying etiology for 90% of patients with hypercalcemia. PHPT patients have traditionally been characterized as being symptomatic or asymptomatic. However, we submit that even "asymptomatic" patients may still have clinical features, posing the idea of coining asymptomatic disease as a misnomer. This paper presents a systematic review and meta-analysis elucidating the differences between asymptomatic and symptomatic PHPT in the literature. Methods: A comprehensive literature search was conducted in PubMed, Cochrane, and Web of Science databases for articles published from 2012 to 2022. Inclusion criteria consisted of all studies comparing symptomatic and asymptomatic PHPT patients. Two reviewers independently evaluated the literature using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The level of evidence was determined using the Oxford Center for Level of Evidence-Based Medicine. Data were extracted, and a meta-analysis was performed. I2 index was employed for heterogeneity. Results: There were 18 studies included, with a total of 4238 patients. The average age of patients included was 56.37, with 25.7% of the cohort being male. Several studies reported clinical features even for the "asymptomatic" group. Patients in the symptomatic group tended to have higher levels of PTH and calcium. The asymptomatic group had greater levels of vitamin D. There was observed heterogeneity between the studies. Conclusions: More extreme PTH, calcium values, and low vitamin D levels were seen in patients with symptomatic disease. However, asymptomatic patients occasionally exhibited clinical features. Therefore, the terminology of "asymptomatic" disease is likely inappropriate for these patients.

Metalloprotease ADAM9 cleaves ephrin-B ligands and differentially regulates Wnt and mTOR signaling downstream of Akt kinase in colorectal cancer cells.

Ephrin-B signaling has been implicated in many normal and pathological processes, including neural crest development and tumor metastasis. We showed previously that proteolysis of ephrin-B ligands by the disintegrin metalloprotease ADAM13 is necessary for canonical Wnt signal activation and neural crest induction in Xenopus, but it was unclear if these mechanisms are conserved in mammals. Here, we report that mammalian ADAM9 cleaves ephrin-B1 and ephrin-B2 and can substitute for Xenopus ADAM13 to induce the neural crest. We found that ADAM9 expression is elevated in human colorectal cancer (CRC) tissues and that knockdown (KD) of ADAM9 inhibits the migration and invasion of SW620 and HCT116 CRC cells by reducing the activity of Akt kinase, which is antagonized by ephrin-Bs. Akt is a signaling node that activates multiple downstream pathways, including the Wnt and mTOR pathways, both of which can promote CRC cell migration/invasion. Surprisingly, we also found that KD of ADAM9 downregulates Wnt signaling but has negligible effects on mTOR signaling in SW620 cells; in contrast, mTOR activity is suppressed while Wnt signaling remains unaffected by ADAM9 KD in HCT116 cells. These results suggest that mammalian ADAM9 cleaves ephrin-Bs to derepress Akt and promote CRC migration and invasion; however, the signaling pathways downstream of Akt are differentially regulated by ADAM9 in different CRC cell lines, reflecting the heterogeneity of CRC cells in responding to manipulations of upstream Akt regulators.

Study of the Efficacy of Uptitrating Teneligliptin Dose from Standard Dose (20 mg) to High Dose (40 mg) in Patients with Type II Diabetes Mellitus.

AIM: To study the efficacy of uptitrating the dose of Teneligliptin from 20 to 40 mg in patients with type II diabetes mellitus. METHOD: A retrospective, comparative analysis was undertaken in 853 type II diabetes mellitus patients (499 males and 354 females) who had follow-up records for more than 6 months. These patients were uncontrolled after use of atleast three oral antidiabetic drugs (OADs) and Teneligliptin 20 mg was added as the fourth drug. Patients who remained uncontrolled with the addition of 20 mg of Teneligliptin at the end of 3 months and were switched to receive 40 mg of Teneligliptin daily were included in this study. Results were analyzed at 3 and 6 months to ascertain efficacy of high-dose (40 mg) Teneligliptin. All other OADs remained the same in both groups. In all patients, the fasting blood glucose, postprandial blood glucose, and hemoglobin A1c (HbA1C) were evaluated and compared. RESULT: A total of 853 patients whose dose of Teneligliptin was increased from 20 to 40 mg were included in the study. At the end of 3 months after using Teneligliptin 40 mg, mean reduction in HbA1C was 0.5% (p-value 0.154). Similarly, mean reduction in fasting blood sugar (FBS) and postprandial blood sugar (PPBS) was 6.5 and 3.6 mg/dL, respectively (p-value 0.234 and 0.143). At the end of 6 months after using Teneligliptin 40 mg HbA1C showed no change but mean FBS and PPBS showed a modest reduction of 14.6 and 14 mg/dL, respectively (p-value < 0.001). CONCLUSION: The results of our study show that there was no statistically significant improvement in glycemic parameters when dose of Teneligliptin was increased from 20 to 40 mg at 3 months. But at 6 months, the FBS and PPBS showed a modest reduction of 14.6 and 14 mg/dL, respectively (p-value < 0.001) but the HbA1C showed no change.

Phylogenetic and spatial distribution of evolutionary diversification, isolation, and threat in turtles and crocodilians (non-avian archosauromorphs).

BACKGROUND: The origin of turtles and crocodiles and their easily recognized body forms dates to the Triassic and Jurassic. Despite their long-term success, extant species diversity is low, and endangerment is extremely high compared to other terrestrial vertebrate groups, with ~ 65% of ~ 25 crocodilian and ~ 360 turtle species now threatened by exploitation and habitat loss. Here, we combine available molecular and morphological evidence with statistical and machine learning algorithms to present a phylogenetically informed, comprehensive assessment of diversification, threat status, and evolutionary distinctiveness of all extant species. RESULTS: In contrast to other terrestrial vertebrates and their own diversity in the fossil record, the recent extant lineages of turtles and crocodilians have not experienced any global mass extinctions or lineage-wide shifts in diversification rate or body-size evolution over time. We predict threat statuses for 114 as-yet unassessed or data-deficient species and identify a concentration of threatened turtles and crocodilians in South and Southeast Asia, western Africa, and the eastern Amazon. We find that unlike other terrestrial vertebrate groups, extinction risk increases with evolutionary distinctiveness: a disproportionate amount of phylogenetic diversity is concentrated in evolutionarily isolated, at-risk taxa, particularly those with small geographic ranges. Our findings highlight the important role of geographic determinants of extinction risk, particularly those resulting from anthropogenic habitat-disturbance, which affect species across body sizes and ecologies. CONCLUSIONS: Extant turtles and crocodilians maintain unique, conserved morphologies which make them globally recognizable. Many species are threatened due to exploitation and global change. We use taxonomically complete, dated molecular phylogenies and various approaches to produce a comprehensive assessment of threat status and evolutionary distinctiveness of both groups. Neither group exhibits significant overall shifts in diversification rate or body-size evolution, or any signature of global mass extinctions in recent, extant lineages. However, the most evolutionarily distinct species tend to be the most threatened, and species richness and extinction risk are centered in areas of high anthropogenic disturbance, particularly South and Southeast Asia. Range size is the strongest predictor of threat, and a disproportionate amount of evolutionary diversity is at risk of imminent extinction.

Efficacy of DPP4i as the Fourth Drug in the Management of Type2 Diabetes Mellitus in Asian Indians Poorly Controlled by Use of at least 3 Oral Antidiabetic Drugs.

AIM: To evaluate the efficacy of DPP-4 inhibitors (DPP-4i) as the fourth drug in Asian Indian type2 DM patients uncontrolled inspite of using at least 3 oral anti diabetic drugs. METHODS: A retrospective analysis of 7858 T2DM patients, who received a DPP-4i (Sitagliptin, Vildagliptin, Teneligliptin, Linagliptin and Saxagliptin) as the fourth drug to achieve glycemic control was undertaken. Patients with inadequate glycaemic control despite receiving optimum doses of at least any other three OADs were included in this analysis. RESULTS: Patients were subdivided into 5 groups, based on the DPP-4i used for treatment: Sitagliptin (n=4787), Vildagliptin (n=2205), Teneligliptin (n=775), Linagliptin (n=64) and Saxagliptin (n=27). The mean fasting blood glucose (FPG) was 160.9 ± 20.4 mg/dl and mean post prandial glucose (PPG) was 227.8 ± 26.3 mg/dl. The mean baseline HbA1c was 8.2 ± 1.5 %. The mean duration required to control diabetes with all DPP-4i was 8.2 weeks with significantly lesser time with Sitagliptin (6.8 weeks, p<0.001). 81.5% of the total cases responded to treatment with a DPP-4i (P <0.05). At the end of the monitoring period, there was significant reduction in mean FPG by-28.1 ± 16.1 mg/dL(P=0.001), mean PPG by -55.3 ± 17.0 mg/dL(P=0.001), and mean HbA1c by -1.2 ± 0.7 (P= 0.001). There was no significant difference between the groups with respect to reduction in PPG and HbA1c. CONCLUSION: DPP-4 inhibitors are effective in achieving desired glycaemic goals even when used as a fourth drug in patients with inadequate glycaemic control despite receiving an optimum dose of at least 3 OADs.

Comparative glandular trichome transcriptome-based gene characterization reveals reasons for differential (-)-menthol biosynthesis in Mentha species.

The genes involved in menthol biosynthesis are reported earlier in Mentha × piperita. But the information on these genes is not available in Mentha arvensis. To bridge the gap in knowledge on differential biosynthesis of monoterpenes leading to compositional variation in the essential oil of these species, a comparative transcriptome analysis of the glandular trichome (GT) was carried out. In addition to the mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathway genes, about 210 and 196 different terpene synthases (TPSs) transcripts were identified from annotation in M. arvensis and M. × piperita, respectively, and correlated to several monoterpenes present in the essential oil. Six isoforms of (-)-menthol dehydrogenases (MD), the last enzyme of the menthol biosynthetic pathway, were identified, cloned and characterized from the transcriptome data (three from each species). Varied expression levels and differential enzyme kinetics of these isoforms indicated the nature and composition of the product, as these isoforms generate both (-)-menthol and (+)-neomenthol from (-)-menthone and converts (-)-menthol to (-)-menthone in the reverse reaction, and hence together determine the quantity of (-)-menthol in the essential oil in these two species. Several genes for high value minor monoterpenes could also be identified from the transcriptome data.

Long term in vitro biostability of segmented polyisobutylene-based thermoplastic polyurethanes.

Long term in vitro biostability of thermoplastic polyurethanes (TPUs) containing mixed polyisobutylene (PIB)/poly(tetramethylene oxide) (PTMO) soft segment was studied under accelerated conditions in 20% H(2)O(2) solution containing 0.1M CoCl(2) at 50 °C to predict resistance to metal ion oxidative degradation (MIO) in vivo. The PIB-based TPUs showed significant oxidative stability as compared to the commercial controls Pellethane 2363-55D and 2363-80A. After 12 weeks in vitro the PIB-PTMO TPUs with 10-20% PTMO in the soft segment showed 6-10% weight loss whereas the Pellethane TPUs degraded completely in about 9 weeks. Attenuated total reflectance Fourier transform infrared spectroscopy confirmed the degradation of Pellethane samples via MIO by the loss of the ∼1110 cm(-1) aliphatic C-O-C stretching peak height attributed to chain scission, and the appearance of a new peak at ∼1174 cm(-1) attributed to crosslinking. No such changes were apparent in the spectra of the PIB-based TPUs. The PIB-based TPUs exhibited 10-30% drop in tensile strength compared to 100% for the Pellethane TPUs after 12 weeks. The molecular weight of the PIB-based TPUs decreased slightly (10-15%) at 12 weeks. The Pellethane TPUs showed a dramatic decrease in M(n) and an increase in low molecular weight degradation product. Scanning electron microscopy (SEM) showed severe cracking in the Pellethane samples after 2 weeks, whereas the PIB-based TPUs exhibited a continuous surface morphology. The weight loss, tensile, and SEM data correlate well with each other and indicate excellent biostability of these materials.

Improved method of in vitro regeneration in Leucaena leucocephala - a leguminous pulpwood tree species.

Leucaena leucocephala is a fast growing multipurpose legume tree used for forage, leaf manure, paper and pulp. Lignin in Leucaena pulp adversely influences the quality of paper produced. Developing transgenic Leucaena with altered lignin by genetic engineering demands an optimized regeneration system. The present study deals with optimization of regeneration system for L. leucocephala cv. K636. Multiple shoot induction from the cotyledonary nodes of L. leucocephala was studied in response to cytokinins, thidiazuron (TDZ) and N(6)-benzyladenine (BA) supplemented in half strength MS (½-MS) medium and also their effect on in vitro rooting of the regenerated shoots. Multiple shoots were induced from cotyledonary nodes at varied frequencies depending on the type and concentration of cytokinin used in the medium. TDZ was found to induce more number of shoots per explant than BA, with a maximum of 7 shoots at an optimum concentration of 0.23 µM. Further increase in TDZ concentration resulted in reduced shoot length and fasciation of the shoots. Liquid pulse treatment of the explants with TDZ did not improve the shoot production further but improved the subsequent rooting of the shoots that regenerated. Regenerated shoots successfully rooted on ½-MS medium supplemented with 0.54 µM α-naphthaleneacetic acid (NAA). Rooted shoots of Leucaena were transferred to coco-peat and hardened plantlets showed ≥ 90 % establishment in the green house.

Antimelanomal activity of the copper(II) complexes of 1-substituted 5-amino-imidazole ligands against B16F10 mouse melanoma cells.

The copper complexes of 5-amino-imidazole ligands were prepared and characterized by various spectroscopic techniques. The ligand geometry around the copper(II) centre is square pyramidal based on N2O2 donor atoms and a coordinated water molecule at the apex. Single crystal X-ray structures were determined for both ligands. Ligands and copper complexes exhibited dose-dependent antiproliferative effects on the growth of B16F10 melanoma cells line but lower IC50 values were observed for the copper complexes.