Genistein: A promising phytoconstituent with reference to its bioactivities.

Genistein, a potent phytoconstituent, has garnered significant attention for its diverse bioactivities, making it a subject of extensive research and exploration. This review delves into the multifaceted properties of genistein, encompassing its antioxidant and anticancer potential. Its ability to modulate various cellular pathways and interact with diverse molecular targets has positioned it as a promising candidate in the prevention and treatment of various diseases. This review provides a comprehensive examination of Genistein, covering its chemical properties, methods of isolation, synthesis, therapeutic attributes with regard to cancer management, and the proposed mechanisms of action as put forth by researchers.

A Comprehensive Review of Various Therapeutic Strategies for the Management of Skin Cancer.

Skin cancer (SC) poses a global threat to the healthcare system and is expected to increase significantly over the next two decades if not diagnosed at an early stage. Early diagnosis is crucial for successful treatment, as the disease becomes more challenging to cure as it progresses. However, identifying new drugs, achieving clinical success, and overcoming drug resistance remain significant challenges. To overcome these obstacles and provide effective treatment, it is crucial to understand the causes of skin cancer, how cells grow and divide, factors that affect cell growth, and how drug resistance occurs. In this review, we have explained various therapeutic approaches for SC treatment via ligands, targeted photosensitizers, natural and synthetic drugs for the treatment of SC, an epigenetic approach for management of melanoma, photodynamic therapy, and targeted therapy for BRAF-mutated melanoma. This article also provides a detailed summary of the various natural drugs that are effective in managing melanoma and reducing the occurrence of skin cancer at early stages and focuses on the current status and future prospects of various therapies available for the management of skin cancer.

Endoscopic classification system of pars tensa retractions.

BACKGROUND: Previous classification systems of pars tensa retractions have not consistently incorporated ossicular erosion or the presence of cholesteatoma. OBJECTIVE: This study aimed to illustrate our classification of pars tensa retractions, which is more precise than previous systems, with aided use of the endoscope. METHODS: A retrospective study was carried out on 200 ears of 170 patients whose pars tensa retractions had been documented at a tertiary otological referral centre. RESULTS: A classification system was developed. Pars tensa retractions were divided into the following subcategories: grade 0, grade 1, grade 2a, grade 2b, grade 3a, grade 3b, grade 3c, grade 4a, grade 4b, grade 4c, grade 5a, grade 5b and grade 5c. CONCLUSION: This classification system was able to accommodate all pars tensa retractions. The distribution of grades of pars tensa retractions was based on ossicular status and the presence or absence of cholesteatoma. It is therefore a more applicable, and functionally based system than previous alternatives.

Management of attic retraction pockets.

OBJECTIVE: Attic retraction pockets, classified by degree of invasion and erosion, are reconstructed here as outlined by attic retraction pocket grade. METHOD: Attic retraction pocket grade, surgical management, subsequent conditions of tympanic membrane and middle ear, and improvement of air-bone gap pure tone average were recorded. RESULTS: Our management strategy, based on attic retraction pocket grade, was applied to 200 ears: 44 grade I ears had non-surgical management and 156 grade II-V ears had surgical management. All 200 ears were followed up for 36-240 months, showing only 1 attic retraction pocket reformation and 1 adhesive otitis media (complication rate of 1 per cent), and improved air-bone gaps (p < 0.05). An earlier series of 50 grade IV attic retraction pockets used atticotomy with epitympanic reconstruction. These showed attic retraction pocket recurrence or cholesteatoma onset in 34 ears (68 per cent). When these ears were revised per protocol, there was no evidence of cholesteatoma thereafter. CONCLUSION: Reconstruction of the ossicles and scutal defect according to attic retraction pocket grade shows long-term stability of the tympanic membrane, middle ear and hearing.

Liposomes in the Targeted Gene Therapy of Cancer: A Critical Review.

Cancer immunotherapy has advanced significantly in recent years. Nanocarriers like liposomes can improve cancer immunotherapy and even stronger immune responses by improving cell type-specific distribution. Liposomes are lipid bilayer vesicles that are biodegradable and biocompatible and are often used as smart delivery systems for both hydrophobic and hydrophilic bioactive. Whereas the idea of employing liposomes for administering drugs has been known since the 1960s, the early 2000s saw continuing technological advances and formulations for drug entrapment and manufacturing. Modern deterministic studies have tried discovering more about how genetic material is delivered through liposomes. Liposomes' interactions with cells are still a bit of mystery. Liposome-mediated transmission of genetic material experiences systemic impediments perlysosomal degradation, endosomal escape, and nuclear uptake. Controlling the physical architecture and chemical properties of liposome structures, such as lipid-to-DNA charge, ester bond composition, size, and ligand complexation structure, is critical for targeting liposomes' success as vehicles for gene delivery. This analysis focuses on advancements in ligand-targeted liposomes and theranostic (diagnostic) liposomes for cancer diagnosis and treatment. This review will explore the numerous transgene mechanisms and molecular targets implicated in cancer cell death and the associated benefits of using liposomal formulations throughout the years. This sequence of breakthroughs will interest aspiring researchers and the pharmaceutical industry involved in liposome development.

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.

A Unified Classification of Middle Ear and Petrous Bone Congenital Cholesteatomas.

BACKGROUND: The aim of this study was to classify congenital cholesteatoma along an entire spectrum of involvement ranging from the middle ear to petrous apex. METHODS: A total of 131 patients (85 adults and 46 children) underwent operations for congenital cholesteatoma over the duration of 27 years. RESULTS: For most cases, middle ear mucosa was normal, the first ossicle eroded by the mass was the stapes, and the mastoid air cell system was well-pneumatized on intraoperative and radiographic views. Totally 34% of patients presented with facial nerve weakness and 45% of these cholesteatomas arose from the supralabyrinthine area (32.8%) and from the petrous apex (12.2%). CONCLUSION: In this unified classification system, the otologist sees congenital cholesteatoma as a continuum, with facial nerve involvement and anacusis as part of the picture. This system of congenital cholesteatoma accommodates the supralabyrinthine and petrous bone locations of the disease.

The Thickness of the facial Nerve Sheath Consistently Varies by Region in Its Intra-Tympanic Course on Cadaveric Study.

OBJECTIVES: Iatrogenic removal of intra-temporal disease processes, such as cholesteatoma and keratosis obturans, can be challenging when the facial nerve (FN) is involved. Despite this concern about possible FN injury during these procedures, our clinical observation has been that the diseased growth can be cleaned quite easily from the vertical FN epineurium. Therefore, we designed a cadaveric protocol to measure thickness of the FN sheath (epineurium) in horizontal, second genu and vertical FN segments and to correlate these measurements with surgical management of FN disorders. METHODS: Fifty non-fixated (wet) cadaveric temporal bones were dissected over 1 year's time. The intra-temporal FN sheath epineurium was harvested from the mid-horizontal, second genu, and mid-vertical segments. Using a digital micrometric technique, the thickness of each sample was measured. Data analysis was performed using student's two-tailed, dependent t-test. RESULTS: Epineurial nerve sheath thickness was the least in the horizontal segment (mean 0.9 mm, range 0.040-0.140 mm), greater at the second genu (mean 0.19 mm, range 0.010-0.280 mm), and greatest in the vertical segment (mean 0.29 mm, range 0.170-0.570 mm). These differences were statistically significant. CONCLUSION: In cases of cholesteatoma and keratosis obturans involving the vertical FN, the disease process can be separated from the FN sheath because of the sheath thickness in this region. Disease in the horizontal segment involves a thinner sheath and separating the disease process from the nerve is more difficult in this area.

An economic model to assess the value of triclosan-coated sutures in reducing the risk of surgical site infection in a mastectomy in India.

BACKGROUND: The comparison of triclosan-coated sutures (TCS) was made with conventional nonantimicrobial-coated sutures (NCS) to reduce surgical site infection (SSI). This study demonstrates the efficacy and economic outcome of TCS versus NCS for SSIs in mastectomy in India. METHODS: In this retrospective analysis, 100 patients were included for both conditions-TCS and NCS-from a private and public hospital in India. A systematic literature search of available evidence for both SSI incidences and TCS efficacy data in India were gathered. We collected cost data from a private and public hospital, respectively, for mastectomy in India. The cost-effectiveness of TCS in comparison with the conventional NCS was calculated using a decision-tree deterministic model. We performed a one-way sensitivity analysis to compare TCS with NCS. RESULTS: Cost savings with the use of TCS increased with an increase in SSI incidence and an increase in efficacy for mastectomies in both public and private hospitals. We found a base cost saving of Indian rupees (INR) 27,299 at a private hospital and INR 2,958 at a public hospital for mastectomies. The incremental cost of TCS suture was 0.01% in a private hospital whereas 0.17% in a public hospital. CONCLUSION: The use of TCS resulted in reduced SSI incidence and cost savings for mastectomy in India.

Potential of luminescent materials in phototherapy.

Phototherapy is the use of light in the treatment of skin diseases that show improvement upon exposure to natural sunlight or man-made lamps. Artificial phototherapy treatments like Narrow band UVB (NB-UVB) phototherapy, Photochemotherapy by UVA (PUVA) and Targeted phototherapy are safe and widely used for several skin diseases like psoriasis, vitiligo, acne vulgaris, mycosis fungoides etc. Photodynamic therapy (PDT), a specialized phototherapy involves use of efficient photo sensitizers and optical radiations for the treatment of cancer and various other medical maladies. Efficacy of these treatments depends on proper selection of a phototherapy lamp which is decided by the wavelength of light emitted by the luminescent material present in it. These luminescent materials on account of their unique luminescence features of portability, power efficiency, lesser heat generation and durability find widespread application in bioassay and therapy. Here, we have discussed about the potential of various luminescent materials for phototherapy on the basis of their photoluminescence behaviour and also tabulated their application for various dermatoses. A few more luminescent materials are discussed in view of current developments in phototherapy and bioscience.

Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Attic retraction pockets: Classification system.

INTRODUCTION: Although attic retractions have previously been classified into Grades 0 through IV, it is often not possible to assign attic retraction pockets into a single specific category. The present study describes an improved classification system based on otoscopic and endoscopic visualization of the retraction pocket fundus, the ossicular status in the attic, degree of scutal erosion, and the presence or absence of cholesteatoma. MATERIALS AND METHODS: One hundred and fifty-four patients (200 ears) with different grades of attic retraction pockets who were seen by a tertiary referral otology center between August 2015 and July 2018 were selected for this study. OBSERVATIONS: The new classification system (Grades I, IIa, IIb, IIIa, IIIb, IIIc, IVa, IVb, IVc, and V) was applied to these retraction pockets. Pure tone audiometry was obtained. RESULTS: All attic retraction pockets could be classified precisely using the new classification system. Forty-four of 200 (22%) of ears showed Grade I Attic retraction, 18 ears showed Grade IIa (9%), 14 showed Grade IIb (7%), 28 showed Grade IIIa (14%), 12 showed IIIb (6%), 20 showed Grade IIIc (10%), 16 showed grade IVa (8%), 12 showed grade IVb (6%), 28 showed grade IVc (14%), and eight showed grade V (4%) attic retraction pockets. Grades I, IIa, IIb, IIIa, and IVa had no significant hearing loss. Average hearing loss was 42 dB and 52 dB in Grades IIIb and IIIc, 44 dB and 58 dB in Grades IVb and IVc, and 61 dB in Grade V. LEVEL OF EVIDENCE: 5 Laryngoscope, 130: 2034-2039, 2020.

Effective Inexpensive Management of Necrotizing Otitis Externa Is Possible in Resource-Poor Settings.

INTRODUCTION: Necrotizing otitis externa resolves best with antimicrobial treatment. How to care for these patients and monitor their resolution remains a problem. Our protocol in Bangalore can manage these patients inexpensively and well. MATERIALS AND METHODS: Patients who were referred to our patients became the subjects for this paper. They were managed through our protocol, which consists of IV ciprofloxacin and meropenem, weekly labs, weekly examinations, and photodocumention. RESULTS: Fifty-one people presented with necrotizing otitis externa (NOE) between October 2015 and November 2017 and completed our entire protocol. Forty-six had complete resolution of their disease, while 5 had to undergo surgical removal of necrotic bone. Six of 8 patients with facial weakness had improvement in their House-Brackmann scores. Reduction of self-reported nocturnal pain, dissolution of ear canal granulations, and normalization of the erythrocyte sedimentation rate (ESR) proved to be the most accurate indicators of disease regression. CONCLUSION: Patients are monitored closely with review of their otalgia, examination of their canal, repeated ESRs, effective control of their diabetes, and radiological imaging. All this can be done in a resource-poor country, which in turn serves as a model for the wealthier nations.

An efficient method to generate xenograft tumor models of acute myeloid leukemia and hepatocellular carcinoma in adult zebrafish.

Zebrafish is emerging as a promising model for the study of human cancers. Several xenograft models of zebrafish have been developed, particularly in larval stages (<48 h post fertilization) when the immune system of fish is not developed. However, xenografting in adult zebrafish requires laborious and transient methods of immune suppression (γ- irradiation or dexamethasone) that limits engraftment and survival of the tumor or fail to recapitulate specific characteristics of malignancies. Thus, the availability of a simple protocol to successfully engraft adult zebrafish, remains a challenge. The current study addresses this limitation and describes a robust method of xenografting in adult zebrafish. We describe a protocol that involves pre-conditioning of Casper, a pigmentation mutant of zebrafish with busulfan that led to a higher rate of engraftment of hepatocellular carcinoma and acute myeloid leukemia cells. To further ascertain the homing characteristics of the injected cancer cells, we transplanted adult zebrafish by two routes of administration and then studied their compartmentalization. This model presents a valuable alternative to rodents to study the biology of these cancers and also a cost-effective platform for evaluation of potential anti-cancer agents.

Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.

Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of alr in liver organogenesis in zebrafish model. We showed that alr is expressed in liver throughout hepatogenesis. Knockdown of alr through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of alr promotes liver growth. The small-liver phenotype in alr morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive Alr(C131S) mutant promoted liver growth and rescued the liver growth defect of alr morphants. Nevertheless, alr(C131S) is less efficacious in both functions. Meantime, high doses of alr MOs lead to widespread developmental defects and early embryonic death in an alr sequence-dependent manner. These results suggest that alr promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of alr in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of alr expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis.