A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer.

Cancer stands as one of the deadliest diseases, ranking second in terms of its global impact. Despite the presence of numerous compelling theories concerning its origins, none have succeeded in fully elucidating the intricate nature of this ailment. Among the prevailing concerns in today's world, breast cancer proliferation remains a significant issue, particularly affecting females. The abnormal proliferation of the PI3K pathway emerges as a prominent driver of breast cancer, underscoring its role in cellular survival and proliferation. Consequently, targeting this pathway has emerged as a leading strategy in breast cancer therapeutics. Within this context, the present article explores the current landscape of anti-tumour drug development, focusing on structural activity relationships (SAR) in PI3K targeting breast cancer treatment. Notably, certain moieties like triazines, pyrimidine, quinazoline, quinoline, and pyridoxine have been explored as potential PI3K inhibitors for combating breast cancer. Various heterocyclic small molecules are undergoing clinical trials, such as Alpelisib, the first orally available FDA-approved drug targeting PI3K; others include buparlisib, pictilisib, and taselisib, which inhibit class I PI3K. These drugs are used for the treatment of breast cancer but still have various side effects with their high cost. Therefore, the primary goal of this review is to include all current advances in the development of anticancer medicines that target PI3K over-activation in the treatment of breast cancer.

Development of nanoemulgel of 5-Fluorouracil for skin melanoma using glycyrrhizin as a penetration enhancer.

The purpose of this study was to enhance the topical delivery of 5-Fluorouracil (5-FU), a cancer treatment, by developing a nanoemulgel formulation. Glycyrrhizin (GLY), a natural penetration enhancer has been investigated to exhibit synergistic effects with 5-FU in inhibiting melanoma cell proliferation and inducing apoptosis, Hence, GLY, along with suitable lipids was utilized to create an optimized nanoemulsion (NE) based gel. Solubility studies and ternary phase diagram revealed isopropyl myristate (IPM), Span 80, Tween 80 as Smix and Transcutol P as co-surfactant. IPM demonstrates excellent solubilizing properties facilitates higher drug loading, ensuring efficient delivery to the target site.,The optimized formulation consisting of 40 % IPM, 30 % of mixture of Tween80: Span80 (Smix) and 15 % Transcutol P provides with a nanometric size of 64.1 ± 5.13 nm and drug loading of 97.3 ± 5.83 %. The optimized formulation observed with no creaming and breakeing of NE and found thermodynamically stable during different stress conditions (temperatures of 4.0 °C and 45.0 °C) and physical thawing (-21.0 ± 0.50 °C to 20.0 ± 0.50 °C). The NE was then transformed into a nanoemulgel (NEG) using 1.5 % w/w Carbopol base and 0.1 % w/w glycyrrhizin. The ex vivo permeability studies showed significant enhancements in drug permeability with the GLY-based 5-FU-NEG formulation compared to pure 5-FU gel in excised pig skin upto1440 min in PBS 7.4 as receptor media. The IC50 values for Plain 5-FU gel, 5-FU-NEG, and GLY-based 5-FU-NEG were found to be 20 µg/mL, 1.1 µg/mL, and 0.1 µg/mL, respectively in B16F10 cell lines. The percentage intracellular uptake of GLY-5-FU-NEG and 5-FU-NEG was found to be 44.3 % and 53.6 %, respectively. GLY-based 5-FU-NEG formulation showed alterations in cell cycle distribution, in compared to 5-FU-NE gel. The overall findings suggest that the GLY-based 5-FU-NEG holds promise for improving anti-melanoma activity.

Design, synthesis and antidiabetic study of triazole clubbed indole derivatives as α-glucosidase inhibitors.

α -Glucosidase is an enzyme present near the brush boundary of the small intestine that is essential in the hydrolysis of carbohydrates to glucose. Because inhibiting this enzyme slows the release of glucose, α-Glucosidase inhibitors are appealing medications for treating diabetes as a carbohydrate-related illness. The present study includes the design, synthesis and antidiabetic potential of novel triazole based indole derivatives as α-glucosidase inhibitor. Among them, the compound R1 was found to be most potent with promising candidate with IC50 value of 10.1 µM and R2 and R3 showed the good inhibitory potency with IC50 values 12.95 µM, 11.35 µM, respectively when compared to the standard drug acarbose having IC50 value of 13.5 µM. In in vivo studies, body weight of the mice was increased when compared to standard drug acarbose, the blood glucose level of the mice was decreased, same as the total cholesterol level, LDL, and triglycerides level decreased in comparison to standard drug. The level HDL was increased as it is a good cholesterol in comparison to standard drug acarbose. Furthermore, these synthesized compounds were docked with α-glucosidase using PDB ID:3WY1 which showed that compound R1 having good docking score -6.734 kcal/mol and compound R2, R3 showed docking score -6.14, -6.10 kcal/mol, respectively when compared with standard acarbose having docking score -4.55 kcal/mol. R1 showed the similar interaction with amino acid PHE166, GLU271, comparison with standard drug Acarbose. The synthesized compounds have been confirmed for antidiabetic activity and may be used for further development of potent compounds.

l-Theanine ameliorates motor deficit, mitochondrial dysfunction, and neurodegeneration against chronic tramadol induced rats model of Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disease, characterized by loss of dopaminergic neurons in substantia nigra, with deficiency of dopamine in the striatum. Tramadol is safe analgesic but long-term use confirmed to elevate oxidative stress, neuroinflammation, mitochondrial dysfunction, in brain leads to motor deficits. l-Theanine is an active constituent of green tea which prevents neuronal loss, mitochondrial failure and improves dopamine, gamma-aminobutyric acid (GABA), serotonin levels and in the central nervous system (CNS) via antioxidant, anti-inflammatory, and neuromodulatory properties. In the present study, tramadol was injected intraperitoneally to Wister rats for 28 days at a dose of 50 mg/kg. l-Theanine (25, 50, and 100 mg/kg) was administered orally 3 h before tramadol administration from day 14 to day 28. Behavioral analyses including rotarod, narrow beam walk, open field, and grip strength were used to evaluate motor coordination on a weekly basis. On the day 29, all Wistar rats were sacrificed and striatum homogenates were used for biochemical (lipid peroxidation, nitrite, glutathione, glutathione peroxidase activity, superoxide dismutase, catalase, mitochondrial complex I, IV, and cyclic adenosine monophosphate), neuroinflammatory markers (tumor necrosis factor-α, interleukin-1ß, and interleukin-17), and neurotransmitters (dopamine, norepinephrine, serotonin, GABA, and glutamate) analysis. Chronic tramadol treatment caused motor deficits reduced antioxidant enzymes level, increased striatal proinflammatory cytokines release, dysbalanced neurotransmitters, and reduced mitochondrial complex activity I, IV, and cAMP activity. However, l-theanine administration attenuated behavioral, biochemical, neuroinflammatory, neurotransmitters, and mitochondrial activity indicated it as a promising neuroprotective potential against degenerative changes in experimental model of PD.

Variability of particulate organic carbon and assessment of satellite retrieval algorithms over the eastern Arabian Sea.

Particulate organic carbon (POC) and its variability were studied to assess the accuracy of ocean colour retrieval algorithms over the eastern Arabian Sea (EAS) as it controls the carbon sequestration, oxygen minimum zone and biogeochemical (C, N and P) cycles. The seasonality in the physical and biological processes strongly influenced the distribution of POC along the EAS. Higher POC and chlorophyll a (chl a) during the spring inter monsoon (SIM) in the north EAS were due to detrainment bloom. The lower POC:chl a ratios during the winter monsoon (WM) (299.8 ± 190.8) than the SIM (482.1 ± 438.3) were due to the influence of freshly derived organic matter with high nutrient levels. The moderate coefficient of regression values of POC with chl a (R2 = 0.49, N = 59) suggests the importance of dead organic materials in controlling the POC distribution in the EAS. Validation between satellite and in situ POC using the four ocean colour retrieval algorithms showed that the algorithm based on the ratio of remote sensing reflectance (Rrs) performed better (R2 = 0.6, N = 17). It also showed a linear trend of POC with absorption coefficients suggesting it as an optical proxy for the POC retrieval.

Status of mannose-binding lectin (MBL) and complement system in COVID-19 patients and therapeutic applications of antiviral plant MBLs.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a virus called "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)." In the majority of patients, infection with COVID-19 may be asymptomatic or may cause only mild symptoms. However, in some patients, there can also be immunological problems, such as macrophage activation syndrome (CSS) that results in cytokine storm syndrome (CSS) and acute respiratory distress syndrome (ARDS). Comprehension of host-microbe communications is the critical aspect in the advancement of new therapeutics against infectious illnesses. Endogenous animal lectins, a class of proteins, may perceive non-self glycans found on microorganisms. Serum mannose-binding lectin (sMBL), as a part of the innate immune framework, recognizes a wide range of microbial microorganisms and activates complement cascade via an antibody-independent pathway. Although the molecular basis for the intensity of SARS-CoV-2 infection is not generally understood, scientific literature indicates that COVID-19 is correlated with unregulated activation of the complement in terms of disease severity. Disseminated intravascular coagulation (DIC), inflammation, and immune paralysis contribute to unregulated complement activation. Pre-existing genetic defects in MBL and their association with complement play a major role in immune response dysregulation caused by SARS-CoV-2. In order to generate anti-complement-based therapies in Covid-19, an understanding of sMBL in immune response to SARS-CoV-2 and complement is therefore essential. This review highlights the role of endogenous sMBL and complement activation during SARS-CoV-2 infection and their therapeutic management by various agents, mainly plant lectins, since antiviral mannose-binding plant lectins (pMBLs) offer potential applications in the prevention and control of viral infections.

Spermine protects aluminium chloride and iron-induced neurotoxicity in rat model of Alzheimer's disease via attenuation of tau phosphorylation, Amyloid-ß (1-42) and NF-κB pathway.

Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by a gradual decline in cognitive and memory functions of the aged peoples. Long-term exposure to heavy metals (aluminium and iron) cause neurotoxicity by amyloid plaques accumulation, tau phosphorylation, increased oxidative stress, neuroinflammation, and cholinergic neurons degeneration, contributes to the development of AD-like symptoms. The present research work is designed to investigate the neuroprotective effect of spermine in aluminium chloride (AlCl3), and iron (Fe) induced AD-like symptoms in rats. Rats were administered of AlCl3 (100 mg/kg p.o.) alone and in combination with iron (120 µg/g, p.o.) for 28 days. Spermine (5 and 10 mg/kg) through intraperitoneal (i.p.) route was given for 14 days. The recognition and spatial memory impairment were tasted using Morris water maze (MWM), actophotometer, and Novel Object Recognition test (NORT). All the rats were sacrificed on day 29, brains were isolated, and tissue homogenate was used for neuroinflammatory, biochemical, neurotransmitters, metals concentration, and nuclear factor-kappa B (NF-κB) analysis. In the present study, AlCl3 and iron administration elevated oxidative stress, cytokines release, dysbalanced neurotransmitters concentration, and biochemical changes. Rats treated with spermine dose-dependently improved the recognition and spatial memory, attenuated proinflammatory cytokine release, and restored neurotransmitters concentration and antioxidant enzymes. Spermine also mitigated the increased beta-amyloid (Aß42), with downregulation of tau phosphorylation. Furthermore, spermine augmented the hippocampal levels of B cell leukaemia/lymphoma-2 (Bcl-2), diminished nuclear factor-kappa B (NF-κB) and caspase-3 (casp-3) expression. Moreover, spermine exhibited the neuroprotective effect through anti-inflammatory, antioxidant, neurotransmitters restoration, anti-apoptotic Aß42 concentration.

Observational evidence on the coastal upwelling along the northwest coast of India during summer monsoon.

The lesser known coastal upwelling in the North Eastern Arabian Sea (NEAS) during summer monsoon, its associated dynamics and forcing mechanisms is elucidated for the first time using basin scale monthly time-series in-situ and satellite data. The presence of cool upwelled waters along northwest coast of India from July to early October with an associated increase in productivity was evident in both data. The low level Findlater jet blows towards west coast of India with high wind magnitude (10-12 m/s) during summer monsoon generates strong Ekman transport (1416 kg/m/s) at offshore and Ekman pumping velocity (1.349 m/s) at coastal region initiates upwelling. It was identified that the currents and remote forcing also regulate upwelling along the region. Although upwelling seems to exist along the northwest coast, it was weaker (25.5 °C) compared to the southwest coast where the SST dropped to 24 °C. The upwelling was observed in the south during June as a surface process, while it was observed along the northwest coast of India by the end of August. Even though the onset of upwelling in the NEAS and South Eastern Arabian Sea (SEAS) had a lag of two months, the recession of upwelling happened during late and early September respectively. The cause for the lag in the onset and cessation of upwelling between SEAS and NEAS is attributed to the propagation of Kelvin waves and southwest monsoon winds. The study also reveals that temperature and chlorophyll profiles show bi-modal peaks of high and low associated with winter cooling (winter) and upwelling (summer).

Laparoscopic approach in cholecystogastric fistula with cholecystectomy and omental patching: A case report and review.

Cholecystoenteric fistulas are rare complications of cholelithiasis, with cholecystogastric fistulas (CGFs) being the rarest. Recommended treatment is surgery; however, select asymptomatic patients can be managed conservatively. The population frequently involved is old age with multiple comorbidities. Open surgery comes with its added morbidities, especially in this subgroup and hence laparoscopic surgery might be beneficial. Sometimes, these fistulas can be incomplete. Here, we describe a case of incomplete CGF managed by laparoscopic cholecystectomy and omental patching along with a brief review of the literature.

Developments and challenges in dermatology: an update from the Interactive Derma Academy (IDeA) 2019.

The 2019 Interactive Derma Academy (IDeA) meeting was held in Lisbon, Portugal, 10-12 May, bringing together leading dermatology experts from across Europe, the Middle East and Asia. Over three days, the latest developments and challenges in relation to the pathophysiology, diagnosis, evaluation and management of dermatological conditions were presented, with a particular focus on acne, atopic dermatitis (AD) and actinic keratosis (AK). Interesting clinical case studies relating to these key topics were discussed with attendees to establish current evidence-based best practices. Presentations reviewed current treatments, potential therapeutic approaches and key considerations in the management of acne, AK and AD, and discussed the importance of the microbiome in these conditions, as well as the provision of patient education/support. It was highlighted that active treatment is not always required for AK, depending on patient preferences and clinical circumstances. In addition to presentations, two interactive workshops on the diagnosis and treatment of sexually transmitted infections/diseases (STIs/STDs) presenting to the dermatology clinic, and current and future dermocosmetics were conducted. The potential for misdiagnosis of STIs/STDs was discussed, with dermoscopy and/or reflectance confocal microscopy suggested as useful diagnostic techniques. In addition, botulinum toxin was introduced as a potential dermocosmetic, and the possibility of microbiome alteration in the treatment of dermatological conditions emphasized. Furthermore, several challenges in dermatology, including the use of lasers, the complexity of atopic dermatitis, wound care, use of biosimilars and application of non-invasive techniques in skin cancer diagnosis were reviewed. In this supplement, we provide an overview of the presentations and discussions from the fourth successful IDeA meeting, summarizing the key insights shared by dermatologists from across the globe.

Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses.

BACKGROUND: In addition to the extent of atypical keratinocytes throughout the epidermis, actinic keratoses (AKs) are histologically characterized by downward-directed basal-layer expansion. It is not known whether this growth pattern correlates with the risk of developing invasive squamous cell carcinoma (iSCC). OBJECTIVES: To characterize the prevalence of downward-directed basal-layer expansion of AKs adjacent to iSCC. METHODS: The epidermis overlying and adjacent to iSCCs was assessed histologically. We determined the histological grade (AK I-III), basal growth pattern (PRO I-III) and accompanying parameters such as adnexal involvement. RESULTS: Among 307 lesions, 52·4% of AKs were histologically classified as AK grade I, 38·1% as AK II and 6·8% as AK III (χ2 -test, P < 0·001). Only 2·6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25·7%, PRO II in 31·9% and PROIII in 39·4% of cases. Only 2·9% of AKs showed no basal growth (χ2 -test, P < 0·001). In total 118 AKs (48·8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18·6% of cases, PRO II in 30·5% and PRO III in 50·8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0·42). CONCLUSIONS: Basal proliferative AKs, as well as atypical keratinocytes restricted to the lower third of the epidermis, are most commonly seen adjacent to iSCC, with less evidence for full-thickness epidermal dysplasia. Our study supports the important role of dysplastic keratinocytes in the epidermal basal layer and their potential association with iSCC.

How are gender inequalities facing India's one million ASHAs being addressed? Policy origins and adaptations for the world's largest all-female community health worker programme.

BACKGROUND: India's accredited social health activist (ASHA) programme consists of almost one million female community health workers (CHWs). Launched in 2005, there is now an ASHA in almost every village and across many urban centres who support health system linkages and provide basic health education and care. This paper examines how the programme is seeking to address gender inequalities facing ASHAs, from the programme's policy origins to recent adaptations. METHODS: We reviewed all publically available government documents (n = 96) as well as published academic literature (n = 122) on the ASHA programme. We also drew from the embedded knowledge of this paper's government-affiliated co-authors, triangulated with key informant interviews (n = 12). Data were analysed thematically through a gender lens. RESULTS: Given that the initial impetus for the ASHA programme was to address reproductive and child health issues, policymakers viewed volunteer female health workers embedded in communities as best positioned to engage with beneficiaries. From these instrumentalist origins, where the programme was designed to meet health system demands, policy evolved to consider how the health system could better support ASHAs. Policy reforms included an increase in the number and regularity of incentivized tasks, social security measures, and government scholarships for higher education. Residential trainings were initiated to build empowering knowledge and facilitate ASHA solidarity. ASHAs were designated as secretaries of their village health committees, encouraging them to move beyond an all-female sphere and increasing their role in accountability initiatives. Measures to address gender based violence were also recently recommended. Despite these well-intended reforms and the positive gains realized, ongoing tensions and challenges related to their gendered social and employment status remain, requiring continued policy attention and adaptation. CONCLUSIONS: Gender trade offs and complexities are inherent to sustaining CHW programmes at scale within challenging contexts of patriarchal norms, health system hierarchies, federal governance structures, and evolving aspirations, capacities, and demands from female CHWs. Although still grappling with significant gender inequalities, policy adaptations have increased ASHAs' access to income, knowledge, career progression, community leadership, and safety. Nonetheless, these transformative gains do not mark linear progress, but rather continued adaptations.

Evaluation of two histological classifications for actinic keratoses - PRO classification scored highest inter-rater reliability.

BACKGROUND: Actinic keratoses (AKs) can histologically be classified by the extent of atypical keratinocytes throughout the epidermis or their pattern of basal proliferation. Currently, no data on the inter-rater reliability of both scores is available. OBJECTIVE: To evaluate the inter-rater reliability of the two classification schemes; histological grade (AK I-III) and basal proliferation (PRO I-III). METHODS: Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I-III), histological grade (AK I-III) and assumed risk of progression into invasive carcinoma. RESULTS: Overall, of the 54 AKs 16.7% (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall's W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. CONCLUSIONS: Histological classification of basal growth pattern (PRO) showed higher inter-rater reliability compared to the established classification of atypical keratinocytes throughout epidermal layers. Moreover, experienced dermatopathologists considered basal proliferation to be more important in terms of progression risk than upwards directed growth patterns. It should be considered to classify AKs according to their basal proliferation pattern (PRO I-III).

Perception about Medicines among the General Public in the Semi-rural Areas of Nepal.

Background Patients' perceptions and beliefs about medicine are affected by their culture, tradition, socioeconomic status, peer influence, educational level, advertisements among other factors. Objective To explore the perception about medicines among the general public in different semi-rural areas of Nepal. Method Cross-sectional study was conducted at different locations within Kathmandu valley from July 2015 to December 2016; 385 individuals were approached using simple random sampling but only 260, aged 18 years and above, who were taking medicines for their health problems, completed the interviewer-administered survey. Their perceptions about medicines were studied using a structured questionnaire based on the WHO booklet "How to investigate the use of medicines by consumers" and analysed using SPSS version 22. Association between respondents' age, gender, education level and perception were statistically analysed using χ2 test and/or Fisher's exact test and multivariate analysis of variance. Result Sixty-one respondents (23.5%) were in age group 56-65 years. Patients' perceptions of medicine safety based on colour, shape, name of medicine, method of administration, compatibility, etc. was statistically different among respondents with regard to their level of education (p = 0.022). More individuals with lower education believed that expensive medicines were more effective (p < 0.001). Increased level of education made them more aware of negative consequences of reusing previous prescriptions (p=0.039). Conclusion Problems with knowledge about medicines were noted among lesser educated individuals. Based on findings, policy makers may develop educational strategies to increase awareness about medicines.

A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy.

BACKGROUND: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. OBJECTIVES: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF-200 ALA was no worse than that for MAL, within a statistical margin of Δ = -15%. METHODS: The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5-year follow-up. Of 281 randomized patients, 138 were treated with BF-200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm-2 ). The results shown include clinical end points and patients' reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013-003241-42). RESULTS: Of the BF-200 ALA-treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one-sided 97·5% confidence interval of -6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%. CONCLUSIONS: Treatment of nonaggressive BCC with BF-200 ALA-PDT is highly effective and well tolerated with proven noninferiority to MAL-PDT. It demonstrates low recurrence rates after 1 year of follow-up.

Actinic keratosis area and severity index (AKASI) is associated with the incidence of squamous cell carcinoma.

BACKGROUND: Actinic keratoses (AKs) are commonly diagnosed clinically. Actinic keratosis area and severity index (AKASI) is a new easy-to-use tool to assess the severity of AKs on the head. OBJECTIVES: To determine the association between chronically UV-induced tumours such as basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) and AKASI. METHODS: We performed a retrospective analysis of patients who had undergone oncological surgery due to UV-induced tumours and who were assessed for AKASI and Physician's global assessment (PGA) prior to surgery. Statistical analysis was performed to evaluate correlation between AKASI, PGA and invasive carcinomas. RESULTS: Of the 210 patients included, 26 patients had histologically diagnosed SCCs and presented with a median (range) AKASI of 6.9 (0-13.0) and PGA of 2 (0-4). In contrast, the 82 patients with BCCs showed a median (range) AKASI of 3.3 (0-15.2) and PGA of 1 (0-4). The Mann-Whitney U-test showed significant differences (P = 0.0018) between AKASI of patients with SCC and BCC. In addition, we found a significantly higher AKASI in patients with SCC compared to patients with non-invasive lesions like AK and Bowen disease (BD) (P = 0.0275). Spearman's coefficient of rank correlation between AKASI and PGA indicates that these measures of AK severity were strongly correlated (P < 0.0001; r = 0.90; 95% CI 0.865-0.920). CONCLUSIONS: Patients with SCC show significantly higher AKASI than patients with BCC or patients without invasive tumours. Hence, AKASI may be used to stratify risk for developing invasive SCC.

Actinic keratoses show variable histological basal growth patterns - a proposed classification adjustment.

BACKGROUND: Common histological classification schemes of actinic keratoses (AK) do not evaluate growth patterns at basal epidermal aspects of AK. Until now, the importance of basal epidermal growth patterns of AK has not been studied. OBJECTIVE: To investigate the extent of atypical keratinocytes throughout the epidermis and variation in basal growth patterns of AK. METHODS: AK lesions occurring on the head/face from patients seen in routine practice were assessed histologically. We determined histological grade (AK I-III), basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting) and accompanying parameters. RESULTS: Of the 246 lesions included, 28.0% were histologically classified as AK I, 46.7% as AK II and 25.2% as AK III. Approximately 26.4% of the basal growth patterns were classified as crowding (pro I), 49.6% as budding (pro II), 17.9% as papillary sprouting (pro III) and 6.1% without basal directed growth. No significant correlation of the histological AK I-III grading and underlying growth patterns was observed (P = 0.4666). However, adnexal structure involvement (OR = 2.37; 95% CI 1.21-4.65), infiltration (OR = 2.53; 95% CI 1.31-4.90) and increased number of vessels (OR = 2.56; 95% CI 1.42-4.65) were independent positive predictive markers for pro II and pro III basal growth patterns. CONCLUSIONS: Basal growth patterns (pro I-III) in AK do not correlate with the established AK I-III histological grading system. Besides the degree of upward extension, varying degrees of downward extension exist. Histological classification should consider both, upwards and downward growth patterns when assessing AK.

Primary uterine angiosarcoma with "rhabdoid morphology": A case report.

INTRODUCTION: Primary uterine angiosarcoma is a very rare tumour, with only 23 cases described till now. It is a malignant tumour with cells variably recapitulating the morphologic features of an endothelium and expressing immunohistochemical markers of endothelial cells. In general, it is a bulky neoplasm and frequently is at advance stage of disease at presentation. In general, patients with uterine angiosarcoma tend to have a poorer prognosis, mostly related to the aggressive nature and the metastatic potential of these tumours. CASE REPORT: We report a rare case of primary uterine angiosarcoma with unusual rhabdoid morphology in a 41-year-old female, who underwent radical hysterectomy and died of disease after 4 months of treatment. DISCUSSION: We described the differential diagnosis of primary angiosarcoma of the uterus that can pose a diagnostic challenge.

Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study.

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.

A proposed scoring system for assessing the severity of actinic keratosis on the head: actinic keratosis area and severity index.

BACKGROUND: Actinic keratosis (AK) severity is currently evaluated by subjective assessment of patients. OBJECTIVES: To develop and perform an initial pilot validation of a new easy-to-use quantitative tool for assessing AK severity on the head. METHODS: The actinic keratosis area and severity index (AKASI) for the head was developed based on a review of other severity scoring systems in dermatology, in particular the psoriasis area and severity index (PASI). Initial validation was performed by 13 physicians assessing AK severity in 18 AK patients and two controls using a physician global assessment (PGA) and AKASI. To determine an AKASI score, the head was divided into four regions (scalp, forehead, left/right cheek ear, chin and nose). In each region, the percentage of the area affected by AKs was estimated, and the severities of three clinical signs of AK were assessed: distribution, erythema and thickness. RESULTS: There was a strong correlation between AKASI and PGA scores (Pearson correlation coefficient: 0.86). AKASI was able to discriminate between different PGA categories: mean (SD) AKASI increased from 2.88 (1.18) for 'light' to 5.33 (1.48) for 'moderate', 8.28 (1.89) for 'severe', and 8.73 (3.03) for 'very severe' PGA classification. The coefficient of variation for AKASI scores was low and relatively constant across all PGA categories. CONCLUSIONS: Actinic keratosis area and severity index is proposed as a new quantitative tool for assessing AK severity on the head. It may be useful in the future evaluation of new AK treatments in clinical studies and the management of AK in daily practice.