Role of tight junction proteins in shaping the immune milieu of malignancies.

INTRODUCTION: Tight junctions (TJs) and their constituent proteins play pivotal roles in cellular physiology and anatomy by establishing functional boundaries within and between neighboring cells. While the involvement of TJ proteins, such as claudins, in cancer is extensively studied, studies highlighting their interaction with immune system are still meager. Studies indicate that alterations in cytokines and immune cell populations can affect TJ proteins, compromising TJ barrier function and exacerbating pro-inflammatory conditions, potentially leading to epithelial cell malignancy. Disrupted TJs in established tumors may foster a pro-tumor immune microenvironment, facilitating tumor progression, invasion, epithelial-to-mesenchymal transition and metastasis. Although previous literature contains many studies describing the involvement of TJs in pathogenesis of malignancies their role in modulating the immune microenvironment of tumors is just beginning to be unleashed. AREAS COVERED: This article for the first time attempts to discern the importance of interaction between TJs and immune microenvironment in malignancies. To achieve the above aim a thorough search of databases like PubMed and Google Scholar was conducted to identify the recent and relevant articles on the topic. EXPERT OPINION: Breaking the vicious cycle of dysbiosis/infections/chemical/carcinogen-induced inflammation-TJ remodeling-malignancy-TJ dysregulation-more inflammation can be used as a strategy to complement the effect of immunotherapies in various malignancies.

Comparative morphology of tumour microenvironment in claudin-low and claudin-high breast cancers.

BACKGROUND: Claudin-low breast cancers (BCs) exhibit more aggressive behaviour compared to claudin-high types. Claudin-low BCs are often characterized by features such as a higher grade, enrichment of stemness characteristics, and a propensity for metastasis. Tumour microenvironment (TME) defined as the intricate network of surrounding cells, blood vessels, and extracellular matrix components influences the behaviour of cancer cells within the breast tissue. Understanding the TME is crucial for comprehending the aggressive characteristics of claudin-low BCs. METHODS: In this study, we have studied the morphology of immune and non-immune TME using Haematoxylin and eosin (H&E)-stained slides of 15 claudin-low and 12 claudin-high tissue samples of BC. RESULTS: TME of claudin-low BCs was observed to have a significantly higher frequency of retraction clefts (66.6 %; n = 10/15), immature desmoplastic response (40 %; n = 6/15), higher stromal cellularity (60 %; n = 9/15); and fibroblastic proliferation (53.3 %; n = 8/15) with a low prevalence of elastosis (66.6 %; n = 10/15). The immune microenvironment revealed a higher frequency of total (80 %; n = 12/15) as well as stromal (86.67 %; n = 13/15) and intra-tumoural TILs (60 %; n = 9/15) in them. CONCLUSION: The above morphology-based study revealed that claudin-low tumours have unique immune and non-immune TME as compared to claudin-high tumours. Future studies exploring the molecular correlates of each of the above morphological features can help in identifying novel therapeutic targets for the treatment of claudin-low BCs.

Serum Zinc Levels in Women with Polycystic Ovarian Syndrome are Lower as Compared to Those without Polycystic Ovarian Syndrome: A Cohort Study.

Background: Zinc is an essential micronutrient, a vital stabiliser and a cofactor in many enzymes such as superoxide dismutase and phospholipase C and also acts as an antioxidant by protecting the sulfhydryl groups of different proteins and enzymes against free radicals. It is unclear if serum zinc levels are correlated with polycystic ovary syndrome (PCOS) and its pathophysiology, although relation between diabetes and insulin resistance has been established. Aims: This study aimed to investigate circulating serum zinc levels in PCOS subjects compared with non-PCOS subjects. Settings and Design: In this cohort study, PCOS subjects were compared with normal subjects aged between 18 and 35. Materials and Methods: All the included subjects underwent measurement of anthropometric parameters, fasting insulin, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, progesterone, oestrogen and serum zinc levels. These values were taken on days 2-5 of the menstrual cycle. Statistical Analysis Used: Univariate analysis and linear regression were performed for serum zinc levels and fasting insulin levels in PCOS subjects and non-PCOS subjects using SPSS (version 21) and Microsoft Excel (2019). Results: Serum zinc levels in the PCOS group were lower than in the control group (P = 0.012). Fasting insulin levels in the PCOS group were higher than in non-PCOS subjects (P = 0.001). We found a negative correlation between zinc and fasting insulin (r = -0.580, P < 0.0001) in the normal group and (r = -0.332, P = 0.019) in the PCOS group. A positive correlation was found between body mass index (BMI) and fasting insulin levels in both the PCOS group (r = 0.227, P = 0.112) and normals (r = 0.612, P < 0.0001). A negative statistically significant correlation between BMI and zinc in both the PCOS group (r = -0.378, P = 0.007) and the non-PCOS group (r = -0.7452, P < 0.0001) was seen. Conclusion: The data suggest that serum zinc levels were found to be lower in PCOS subjects as compared to normal controls and evaluation of these levels may indicate that zinc has a vital role in PCOS pathophysiology.

Maternal Mortality and COVID-19 Pandemic: Looking Beyond SARS CoV-2 Infection.

Objective: To study the impact of COVID-19 pandemic on maternal mortality ratio, aetiological and modifiable factors for maternal mortality and key interventions performed. Method: Retrospective exploratory study evaluating maternal mortality between April to November 2020 (study group) and 2019 (control group). Results: Demographic variations existed in the two groups. Increased maternal age and illiteracy were significantly more in the study group. Maternal mortality ratio (MMR) was significantly high in the study group (792 vs. 296 p value = 0.0). Hemorrhage accounted for 20% and COVID-19-related maternal deaths accounted for 15% deaths in the study group. Level 3 delay (delay in receiving care/inadequate care) was observed in 35% in the study group and 28% in control group (p value = 0.349). 17.5% of mothers in the study group as compared to 8% of control group were dead on arrival to hospital though not statistically significant (p value = 0.28). Significantly more women in study group died within 24 h of admission (45% vs. 20%, p value 0.04). Among the key interventions, the use of supplemental oxygen was significantly high in study group (p value = 0.02). Conclusion: Maternal mortality ratio was high in the pandemic year because of a significant decline in hospital delivery rate. The lesson learnt from this pandemic needs to be documented to guide better planning in the future to face similar situations.

Aspirin as a potential drug repurposing candidate targeting estrogen receptor alpha in breast cancer: a molecular dynamics and in-vitro study.

Estrogen receptor alpha (ERα) is expressed by 70% of breast cancers (BCs). Any deregulation in ERα signaling is crucial for the initiation and progression of BC. Because of development of resistance to anti-estrogenic compounds, repurposing existing drugs is an apt strategy to avoid a long drug-discovery process. Substantial epidemiologic evidence suggests that Aspirin use reduces the risk of different cancers including BC, while its role as an adjuvant or a possible antineoplastic agent in cancer treatment is being investigated. In this study, we attempted to explore possibilities of ERα inhibition by Aspirin which may act through competitive binding to the ligand binding domain (LBD) of ERα. A list of 48 ERα-LBD crystal structures bound with agonists, antagonists, and selective ER modulators (SERMs) was thoroughly analysed to determine interaction patterns specific to each ligand category. Exhaustive docking and 500 ns molecular dynamics (MD) studies were performed on three ERα - Aspirin complexes generated using agonist, antagonist, and SERM-bound crystal structures. Besides, three ERα crystal structures bound to agonist, antagonist, and SERM respectively were also subjected to MD simulations. Aspirin showed good affinity to LBD of ERα. Comparative analyses of binding patterns, conformational changes and molecular interaction profiles from the docking results and MD trajectories suggests that Aspirin was most stable in complex generated using SERM bound crystal structure of ERα and showed interactions with Gly-521, Ala-350, Leu-525 and Thr-347 like SERMs. In addition, in-vitro assays, qPCR, and immunofluorescent assay demonstrated the decline in the expression of ERα in MCF-7 upon treatment with Aspirin. These preliminary bioinformatical and in-vitro findings may form the basis to consider Aspirin as a potential candidate for targeting ERα, especially in tamoxifen-resistant cancers.Communicated by Ramaswamy H. Sarma.

An image analysis approach to characterize micronuclei differences in different subtypes of breast cancer.

BACKGROUND: Micronuclei (MN) have been used as screening, diagnostic and prognostic markers in multiple cancer types, including breast cancer (BC). However, the question that the MN present in all subtypes of BC are similar or different remains unanswered. We thus hypothesized that MN present in different subtypes of BC may differ in their contents which may be visible as differences in their morphologic and morphometric features. This study was thus carried out with the aim to identify the differences between MN morphometry, complexity, and texture in different subtypes of BC, such as estrogen and progesterone receptor-positive (ER+/PR+; MCF-7, T-47D), human epidermal growth factor receptor-positive (Her2 +;SKBR3) and triple-negative BC (TNBC; MDA-MB-231, MDA-MB-468) cell lines (CLs) by ImageJ software. METHODS: For analysis of MN dimensions, MN irregularity, and texture, we used morphometry and two mathematical computer-assisted algorithms, i.e., fractal dimension (FD) and grey level co-occurrence matrix (GLCM) of ImageJ software. RESULTS: MN area and perimeter values showed differences in the size of MN in different subtypes of BC, with the largest MN in TNBC CLs. GLCM parameters (entropy, angular second moment, inverse difference moment, contrast, and correlation) showed highly heterogenous texture in case of TNBC MN as compared to the others. FD analysis also revealed more complexity and irregularity in MN found in TNBC cells. CONCLUSION: The study for the first time showed morphometric, architectural and texture related differences amongst MN present in different subtypes of BC. The above may reflect differences in their composition and contents. Further, these differences may point towards the distinct mechanisms involved in the formation of MN in different subtypes of BC that need to be explored further.

Bottom-up approach to explore alpha-amylase assisted membrane remodelling.

Soluble alpha-amylases play an important role in the catabolism of polysaccharides. In this work, we show that the malt α -amylase can interact with the lipid membrane and further alter its mechanical properties. Vesicle fluctuation spectroscopy is used for quantitative measurement of the membrane bending rigidity of phosphatidylcholines lipid vesicles from the shape fluctuation based on the whole contour of Giant Unilamellar Vesicles (GUVs). The bending rigidity of the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipid vesicles in water increases significantly with the presence of 0.14 micromolar alpha-amylase (AA) in the exterior solution. It appears that the enzyme present in the external solution interacts with the outer layer of the bilayer membrane, leading to an asymmetry of the solution on either side of the bilayer membrane and altering its elasticity. At AA concentration of 1.5 micromolars and above, changes in the morphology of the GUV membrane are observed. The interaction between AA in the external solution and the external leaflet causes the bilayer membrane to curve spontaneously, leading to the formation of outbuds, giving a positive spontaneous curvature of C0 ≤ 0.05 µm-1 at ≈ 1 mg / ml of the AA concentration. We validate and characterize its concentration-dependent role in stabilizing the membrane curvature. Our findings indicate that the involvement of the enzyme, depending on the concentration, can have a considerable effect on the mechanical characteristics of the membrane.

Impact of Action Taken in Response to Stillbirth Audit: A Success Story.

Objectives: Study the impact of intra-facility interventions on the modifiable factors causing stillbirths (SB), using point-of-care quality improvement (POCQI) methodology. Material and Methods: Stillbirth data during the 9 months pre-intervention period were reviewed to identify the common preventable causes. Two interventions, namely, ultrasound at 34-36 weeks gestation and intrapartum monitoring on a common customized labor chart for all health-care providers, were done. Post-intervention data were collected to observe the impact of the interventions. Results: The stillbirth rate reduced from 212/5940 deliveries (35.7/1000) in the pre-intervention period to 165/5993 deliveries (27.7/1000) in the post-intervention period (p = 0.011). The intra-facility failure to identify FGR significantly reduced in the post-intervention group (p = 0.033), leading to 63% (RR 0.37) reduction in its risk. Using a common customized labor chart led to a significant decline in the inadequate monitoring as a provider-related cause of stillbirth (p < 0.001) leading to its 42% decline as contributor to modifiable cause of SB (RR 0.48). Conclusion: Reviewing the perinatal death surveillance response (PDSR) data, identifying gaps in care, and using improvement methodology for instituting corrective measures play an important role in reducing intramural stillbirths.

Ocular and Neuro-ophthalmic Manifestations Post COVID-19 Infection.

A 39-year-old male with a history of COVID-19 infection presented with ocular manifestations: dendritic ulcer in the left eye cornea followed by diplopia in the same eye. Extraocular motility was restricted in the levo-lateral gaze with maximum diplopia measuring 25∆ exotropia. Slit lamp biomicroscopy showed dendritic patterned lesion with diffused superficial punctate keratitis in the cornea. There are various reports associated with COVID-19 and the neuro-ophthalmic system. Although the clinicopathological aspect of COVID-19 and the neurological system is still to explicate. However, the patient showed gradual improvement with topical and systemic antiviral therapy and orthoptic exercise. This points to the need for detailed neurological and ophthalmic workup in symptomatic COVID-19 patients. Taking the risk of viral spread into serious consideration, a thorough evaluation is though mandatory. Keywords: COVID-19; dendritic ulcer; lateral rectus palsy; superficial punctate keratopathy.

Perceiving placental ultrasound image texture evolution during pregnancy with normal and adverse outcome through machine learning prism.

INTRODUCTION: The objective was to perform placental ultrasound image texture (UPIA) in first (T1), second(T2) and third(T3) trimesters of pregnancy using machine learning( ML). METHODS: In this prospective observational study the 2D placental ultrasound (US) images from 11-14 weeks, 20-24 weeks, and 28-32 weeks were taken. The image data was divided into training, validating, and testing subsets in the ratio of 80%, 10%, and 10%. Three different ML techniques, deep learning, transfer learning, and vision transformer were used for UPIA. RESULTS: Out of 1008 cases included in the study, 59.5% (600/1008) had a normal outcome. The image texture classification was compared between T1&T2, T2 &T3 and T1&T3 pairs. Using Inception v3 model, to classify T1& T2 images, gave the accuracy, Cohen Kappa score of 83.3%, 0.662 respectively. The image classification between T1&T3 achieved best results using EfficientNetB0 model, having the accuracy, Cohen Kappa score, sensitivity and specificity of 87.5%, 0.749, 83.4%, and 88.9% respectively. Comparison of placental image texture among cases with materno-fetal adverse outcome and controls was done using Efficient Net B0. The F1 score, was found to be 0.824 , 0.820, and 0.892 in T1, T2 and T3 respectively. The sensitivity and specificity of the model was 77.4% at 80.2% at T1 but increased to 81.0% and 93.9% at T2 &T3 respectively. DISCUSSION: The study presents a novel technique to classify placental ultrasound image texture using ML models and could differentiate first and third-trimester normal placenta and normal and adverse pregnancy outcome images with good accuracy.

Highly Responsive Near-Infrared Si/Sb2Se3 Photodetector via Surface Engineering of Silicon.

The development of imaging technology and optical communication demands a photodetector with high responsiveness. As demonstrated by microfabrication and nanofabrication technology advancements, recent progress in plasmonic sensor technologies can address this need. However, these photodetectors have low optical absorption and ineffective charge carrier transport efficiency. Sb2Se3 is light-sensitive material with a high absorption coefficient, making it suitable for photodetector applications. We developed an efficient, scalable, low-cost near-infrared (NIR) photodetector based on a nanostructured Sb2Se3 film deposited on p-type micropyramidal Si (made via the wet chemical etching process), working on photoconductive phenomena. Our results proved that, at the optimized thickness of the Sb2Se3 layer, the proposed Si micropyramidal substrate enhanced the responsivity nearly two times, compared with that of the Sb2Se3 deposited on a flat Si reference sample and a glass/Sb2Se3 sample at 1064 nm (power density = 15 mW/cm2). More interestingly, the micropyramidal silicon-based device worked at 0 V bias, paving a path for self-bias devices. The highest specific detectivity of 2.25 × 1015 Jones was achieved at 15 mW/cm2 power density at a bias voltage of 0.5 V. It is demonstrated that the enhanced responsivity was closely linked with field enhancement due to the Kretschmann configuration of Si pyramids, which acts as hot spots for Si/Sb2Se3 junction. A high responsivity of 47.8 A W-1 proved it suitable for scalable and cost-effective plasmonic-based NIR photodetectors.

Touch imprint smear: A prerequisite to obtain better quality and "true" tumor RNA in breast tissues.

BACKGROUND: RNA is the primary genetic material required for various molecular studies. RNA derived from breast tissue has low quality and quantity compared to that extracted from other tissues. Therefore, optimization of techniques for breast tissue RNA extraction is a challenging but essential requirement. METHODS: RNA was extracted from 60 samples of breast cancer after dividing them into 2 groups. Each tissue was divided into 2 halves for RNA extraction and histopathology respectively. In group 2 RNA was extracted after taking touch imprints whereas group1 was not subjected to any such procedure. Concentration and purity of RNA was assessed by using spectrophotometer and 1% agarose gel followed by RT-PCR for 18 S rRNA and CCND1 gene. RESULTS: Based on microscopic observations of imprints, group 2 samples were further subdivided into 2 subgroups. Group 2 A (n = 30) showing tumor in imprint smears were found to yield best concentration of pure RNA (1846.50 ng/µl and 1.92) as compared to group 2B (n = 15) with no malignancy in imprints (102.61 ng/µl and 1.53). The correlation of imprint smears with their corresponding H&E-stained slides further leads to grouping of each group in 2 groups. RT-PCR analyses showed better melting peaks and high relative expression of CCND1 in group 2 A. CONCLUSION: Touch imprints may provide valuable information regarding presence or absence of tumor in tissue samples being used for extraction of genetic material. This approach can be used as easy, cheap and fast strategy to resolve the doubts associated with RNA being truly representative of the tumor.

Investigating active area dependent high performing photoresponse through thin films of Weyl Semimetal WTe2.

WTe2 is one of the wonder layered materials, displays interesting overlapping of electron-hole pairs, opening of the surface bandgap, anisotropy in its crystal structure and very much sought appealing material for room temperature broadband photodection applications. Here we report the photoresponse of WTe2 thin films and microchannel devices fabricated on silicon nitride substrates. A clear sharp rise in photocurrent observed under the illumination of visible (532 nm) and NIR wavelengths (1064 nm). The observed phoresponse is very convincing and repetitive for ON /OFF cycles of laser light illumination. The channel length dependence of photocurrent is noticed for few hundred nanometers to micrometers. The photocurrent, rise & decay times, responsivity and detectivity are studied using different channel lengths. Strikingly microchannel gives few orders of greater responsivity compared to larger active area investigated here. The responsivity and detectivity are observed as large as 29 A/W and 3.6 × 108 Jones respectively. The high performing photodetection properties indicate that WTe2 can be used as a broad band material for future optoelectronic applications.

Primary fallopian tube endometroid carcinoma: A rare case report.

ABSTRACT: Primary fallopian tube carcinoma is an extremely rare tumor accounting for only 0.14-1.8% of genital tract cancers. A 47-year-old female presented with post-menopausal bleeding and heaviness in the lower abdomen. Imaging revealed the right adnexal mass, suggestive of neoplastic origin. She was prepared for surgery. Per-operatively, there was a solid irregular mass, firm to hard in consistency, around 8 × 5 cm involving the whole of the right fallopian tube, and the right ovary appeared normal. Histopathological examination of the specimen showed endometroid adenocarcinoma of the right fallopian tube. Endometroid carcinoma is important to recognize because it carries the best prognosis of all the fallopian tube cancers. The patient underwent surgery, followed by adjuvant chemotherapy, and was doing well in follow-up.

Development and Validation of a Digital (Peek) Near Visual Acuity Test for Clinical Practice, Community-Based Survey, and Research.

Purpose: Unaddressed near vision impairment (NVI) affects more than 500 million people. Testing near vision is necessary to identify those in need of services. To make such testing readily accessible, we have developed and validated a new smartphone-based near visual acuity (NVA) test: Peek Near Vision (PeekNV). Methods: Two forms of the PeekNV test were developed: (1) quantitative measurement of NVA, and (2) binary screening test for presence or absence of NVI. The validity study was carried out with 483 participants in Sagarmatha Choudhary Eye Hospital, Lahan, Nepal, using a conventional Tumbling "E" Near Point Vision Chart as the reference standard. Bland-Altman limits of agreement (LoA) were used to evaluate test agreement and test-retest repeatability. NVI screening was assessed using Cohen's kappa coefficient, sensitivity, and specificity. Results: The mean difference between PeekNV and chart NVA results was 0.008 logMAR units (95% confidence interval [CI], -0.005 to 0.021) in right eye data, and the 95% LoA between PeekNV and chart testing were within 0.235 and -0.218 logMAR. As a NVI screening tool, the overall agreement between tests was 92.9% (κ = 0.85). The positive predictive value of PeekNV was 93.2% (95% CI, 89.6% to 96.9%), and the negative predictive value 92.7% (95% CI, 88.9% to 96.4%). PeekNV had a faster NVI screening time (11.6 seconds; 95% CI, 10.5 to 12.6) than the chart (14.9 seconds; 95% CI, 13.5 to 16.2; P < 0.001). Conclusions: The PeekNV smartphone-based test produces rapid NVA test results, comparable to those of an accepted NV test. Translational Relevance: PeekNV is a validated, reliable option for NV testing for use with smartphones or digital devices.

Primary Pure Large-Cell Neuroendocrine Carcinoma of the Ovary: A Rare Case Report.

Primary pure large-cell neuroendocrine carcinoma is a rare entity with 17 cases reported till now. A 48-year-old, Para6 Live4, postmenopausal woman presented with complaints of pain abdomen, constipation for 6 months, and postmenopausal bleeding for 1 month. On per abdominal examination, an irregular, hard, fixed, and tender mass was felt in the pelvis corresponding to 32 weeks size gravid uterus. Her magnetic resonance imaging findings were suggestive of a large abdominopelvic mass of size 10.2 cm × 12.7 cm × 14.2 cm with inferior extension into the left adnexa and 3.1 cm × 2.2 cm × 2.1 cm right adnexal mass. Debulking surgery was done. The intraoperative findings were of a large abdominopelvic mass adhered to the sigmoid colon and retroperitoneal space. Histopathological and immunohistochemistry findings were suggestive of bilateral large-cell neuroendocrine carcinoma of ovaries with strong positive for Bcl2, CD56, NSE, PR, and P53. The patient was started on tablet etoposide as adjuvant treatment. After 5 months of primary surgery, contrast-enhanced computed tomography of the chest, abdomen, and pelvis revealed recurrence. She succumbed to her illness 6 months after primary surgery. Owing to its rarity and difficulty in diagnosis, it is suggested that all such cases should be registered at national level and critically analyzed to find the high risk and associated prognostic factors.

Diagnosis of Fungal Keratitis in Low-Income Countries: Evaluation of Smear Microscopy, Culture, and In Vivo Confocal Microscopy in Nepal.

Clinically diagnosing fungal keratitis (FK) is challenging; diagnosis can be assisted by investigations including in vivo confocal microscopy (IVCM), smear microscopy, and culture. The aim of this study was to estimate the sensitivity in detecting fungal keratitis (FK) using IVCM, smear microscopy, and culture in a setting with a high prevalence of FK. In this cross-sectional study nested within a prospective cohort study, consecutive microbial keratitis (MK) patients attending a tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. IVCM and corneal scrapes for smear microscopy and culture were performed using a standardised protocol. Smear microscopy was performed using potassium hydroxide (KOH), Gram stain, and calcofluor white. The primary outcomes were sensitivities with 95% confidence intervals [95% CI] for IVCM, smear microscopy and culture, and for each different microscopy stain independently, to detect FK compared to a composite referent. We enrolled 642 patients with MK; 468/642 (72.9%) were filamentous FK, 32/642 (5.0%) were bacterial keratitis and 64/642 (10.0%) were mixed bacterial-filamentous FK, with one yeast infection (0.16%). No organism was identified in 77/642 (12.0%). Smear microscopy had the highest sensitivity (90.7% [87.9-93.1%]), followed by IVCM (89.8% [86.9-92.3%]) and culture (75.7% [71.8-79.3%]). Of the three smear microscopy stains, KOH had the highest sensitivity (85.3% [81.9-88.4%]), followed by Gram stain (83.2% [79.7-86.4%]) and calcofluor white (79.1% [75.4-82.5%]). Smear microscopy and IVCM were the most sensitive tools for identifying FK in our cohort. In low-resource settings we recommend clinicians perform corneal scrapes for microscopy using KOH and Gram staining. Culture remains an important tool to diagnose bacterial infection, identify causative fungi and enable antimicrobial susceptibility testing.

Claudins: The Newly Emerging Targets in Breast Cancer.

Claudin-low breast cancers are recently described entities showing low expression of certain claudins and cell adhesion molecules. Claudins constitute the backbone of tight junctions (TJs) formed between 2 cells. Their dysregulation plays a vital role in tumorigenesis. First part of the article focuses on the role of claudins in the TJ organization, their structural-functional characteristics, and post-transcriptional and translational modifications. The latter part of the review attempts to summarize existing knowledge regarding the status of claudins in breast cancer. The article also provides an overview of the effect of claudins on tumor progression, metastasis, stemness, chemotherapy resistance, and their crosstalk with relevant signaling pathways in breast cancer. Claudins can act as 2-edged swords in tumors. Some claudins have either tumor-suppressive/ promoting action, while others work as both in a context-dependent manner. Claudins regulate many important events in breast cancer. However, the intricacies involved in their activity are poorly understood. Post-translational modifications in claudins and their impact on TJ integrity, function, and tumor behavior are still unclear. Although their role in adverse events in breast cancer is recognized, their potential to serve as relevant targets for future therapeutics, especially for difficult-to-treat subtypes of the above malignancy, remains to be explored.

Delay in accessing definitive care for patients with microbial keratitis in Nepal.

Background: The aim of this study was to describe the health-seeking journey for patients with microbial keratitis (MK) in Nepal and identify factors associated with delay. Methods: Prospective cohort study where MK patients attending a large, tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. We collected demographic details, clinical history, and examination findings. Care-seeking journey details were captured including places attended, number of journeys, time from symptom onset, and costs. We compared "direct" with "indirect" presenters, analyzing for predictors of delay. Results: We enrolled 643 patients with MK. The majority (96%) self-referred. "Direct" attenders accounted for only 23.6% (152/643) of patients, the majority of "indirect" patients initially presented to a pharmacy (255/491). Over half (328/643) of all cases presented after at least 7 days. The total cost of care increased with increasing numbers of facilities visited (p < 0.001). Those living furthest away were least likely to present directly (p < 0.001). Factors independently associated with delayed presentation included distance >50 km from the eye hospital [aOR 5.760 (95% CI 1.829-18.14, p = 0.003)], previous antifungal use [aOR 4.706 (95% CI 3.139-5.360)], and two or more previous journeys [aOR 1.442 (95% CI 1.111-3.255)]. Conclusions: Most patients visited at least one facility prior to our institution, with time to presentation and costs increasing with the number of prior journeys. Distance to the eye hospital is a significant barrier to prompt, direct presentation. Based on these findings, improving access to eye care services, strengthening referral networks and encouraging early appropriate treatment are recommended to reduce delay, ultimately improving clinical outcomes.