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Introduction: Vitiligo is nowadays a common hypopigmented skin disorder. Depending on clinical features, vitiligo can be correlated with Shwitra in Ayurveda. The present study evaluates the efficacy of the Virechana therapy to augment the effectiveness of the Bakuchi compound and Khadira Kwatha in Shwitra. Methods: The current study included thirty clinically diagnosed Shwitra patients who were randomly divided into two groups (Group A and Group B) by simple random method with 15 patients in each group. Thirteen patients in Group A and 15 patients in Group B had completed the study. The duration of the trial was 60 days. The assessment was done on the 1st, 30th, and 60th days. Results: The results revealed that intervention in Group A and B showed insignificant results in Rukshata, Daha, and Romparidhwamsi, while, respectively, significant and highly significant in Kandu. There was a highly significant result (P < 0.01 and P < 0.001 for Groups A and B, respectively) for the patches' size and the skin color. During intergroup comparison, the mean difference along with standard deviation (MSD) for size of patches in Group A was 3.76 ± 4.17 and in Group B was 14.26 ± 9.43, showing the highly significant result. Likewise, MSD for the color of skin in group A was 0.76 ± 3.77 and in Group B was 1.53 ± 6.85, showing the intergroup comparison as significant. Conclusion: “Bakuchi Compound” and “Khadira Kwatha” are safe and free from adverse effects in the management of Shwitra. The Virechana Chikitsa augments the effectiveness of this treatment.

RationalePrevious studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission.MethodsWe determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-

BackgroundEczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+).MethodsWhole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation.ResultsEight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR).ConclusionSIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.

Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naive tumor responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains common. Although the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, and the molecular basis of tumor type and pathway selection are still obscure. Here, we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoothened inhibitor-resistant BCCs have an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared with naive or Gorlin syndrome patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature showed increased Ras/MAPK pathway activation. Tissue analysis confirmed an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiated Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines conferred resistance to both canonical (vismodegib) and noncanonical (atypical protein kinase C and MRTF inhibitors) HH pathway inhibitors and conferred sensitivity to MAPK inhibitors. Our results provide insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH-to-Ras/MAPK pathway switching.

Abstract Background Tuberculosis currently stands as the second leading cause of deaths worldwide due to single infectious agent after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The current challenges of drug resistance in tuberculosis highlight an urgent need to develop newer anti-mycobacterial compounds. In the present study, we report the serendipitous discovery of a bacterial laboratory contaminant (LC-1) exhibiting a zone of growth inhibition on an agar plate seeded with Mycobacterium tuberculosis. Results We utilized microbiological, biochemical and biophysical approaches to characterize LC-1 and anti-mycobacterial compound(s) in its secretome. Based on 16S rRNA sequencing and BIOLOG analysis, LC-1 was identified as Staphylococcus hominis, a human bacterial commensal. Anti-mycobacterial activity was initially found in 30 kDa retentate that was obtained by ultrafiltration of culture filtrate (CF). SDS-PAGE analysis of peak fractions obtained by size exclusion chromatography of 30 kDa retentate confirmed the presence of high molecular weight (≥ 30 kDa) proteins. Peak fraction-1 (F-1) exhibited inhibitory activity against M. bovis BCG, but not against M. smegmatis, E. coli and S. aureus. The active fraction F-1 was inactivated by treatment with Proteinase K and α-chymotrypsin. However, it retained its anti-mycobacterial activity over a wide range of heat and pH treatment. The anti-mycobacterial activity of F-1 was found to be maintained even after a long storage (~12 months) at − 20 °C. Mass spectrometry analysis revealed that the identified peptide masses do not match with any previously known bacteriocins. Conclusions The present study highlights the anti-mycobacterial activity of high molecular weight protein(s) present in culture filtrate of LC-1, which may be tested further to target M. tuberculosis. The heat and pH stability of these proteins add to their characteristics as therapeutic proteins and may contribute to their long shelf life. LC-1 being a human commensal can be tested in future for its potential as a probiotic to treat tuberculosis.

Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

Introduction: The superficial infection that involves the hair follicle with bogginess or induration of involved parts of the scalp along with pustules, erosions, crusts, ulcers, and scales resulting in hair fall is known as folliculitis decalvans (FD). This condition accounts for approximately 11% of all cases with primary cicatricial alopecia. Based on clinical features like Keshadhwansha (hair fall) with Harsha (hypersensitivity), Kandu (itching), Toda (pain), FD can be correlated with Raktaja Krimi Vikara (RKV). Observation and results: A 24 years' male patient with the chief complaint of patchy hair loss in the scalp region associated with scale formation, itching, and pain for 2 months. He had a history of pustules-like eruption over the frontal and parietal regions. He tried various topical and oral medications for 8 days but didn't get any sign of improvement and came to NIA hospital for Ayurveda treatment. Due to the signs like pustules over the scalp, hair loss with honey-colored crusting, scarring, mild itching, and pain; he was diagnosed with RKV ∼ FD. After treatment with Ayurveda medicine and leech therapy, complete remission of the scar, lesions, itching, pain, and hair loss was obtained, and there was new hair growth over the scalp with normal distribution. The patient was on follow-up for 33 months with no signs of itching, pain, and hair fall. Conclusion: Complete remission of FD was achieved by Ayurveda medicine along with Jalaukavacharana and it seems highly effective on the basis of remission period compared to contemporary treatment modalities. It is suggested to have further clinical studies with large samples to analyze its effectiveness.

Background: Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging‐to‐treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. Methods: We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient‐derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single‐agent and a combination of PI3K/mTOR inhibitors with PD‐1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single‐cell RNA/TCR sequencing of serially collected biopsies. Results: PI3K/mTOR over‐activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB‐resistant humanized uLMS PDX model, fostering adaptive anti‐tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti‐tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD‐1+ T cells displaying an exhausted phenotype. When combined with anti‐PD‐1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single‐agent anti‐PD‐1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper‐expansion of a cytotoxic CD8+ T‐cell population supported by a CD4+ Th1 niche. Conclusions: Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that forms aggregates (clumps) on solid agar plates and in liquid media. Detergents such as Tween 80/Tyloxapol are considered the gold standard to disrupt clump formation in Mtb cultures. The presence of detergent, however, may generate foam and hinder Mtb aerosolization thus requiring addition of an antifoam agent for optimal Mtb aerosol-based procedures. Aerosol inhalation can be technically challenging, in particular to achieve a reproducible inhaled target dose. In this study, the impact of an antifoam, the silicon antifoaming agent (SAF), on Mtb aerosolization and whole-body mouse aerosol infection was investigated. A comparative study using SAF in a liquid suspension containing Mycobacterium bovis BCG (M. bovis BCG) or Mtb H37Rv did not cause any adverse effect on bacterial viability. Incorporation of SAF during mycobacteria inhalation procedures revealed that aerosolized mycobacterial strains were maintained under controlled environmental conditions such as humidity, temperature, pressure, and airflow inside the aerosol chamber. In addition, environmental factors and spray factors were not affected by the presence of SAF in mycobacterial cultures during aerosolization. Spray factor was significantly less during aerosol procedures with a low-input dose of mycobacteria in comparison to high-dose, as predicted. The mycobacterial load recovered in the biosampler (AGI) was ~2-3 logs lower than nebulizer or input bacterial load. A consistent Mtb bacillary load determined in mouse lungs indicates that SAF does not affect mycobacteria aerosolization during the aerosol generation process. These data confirmed that 1) SAF prevents formation of excessive foam during aerosolization, 2) SAF had no negative impact on mycobacterial viability within aerosol droplets, 3) Mtb droplets within aerosol-generated particles are well within the range required for reaching and depositing deep into lung tissue, and 4) SAF had no negative impact on achieving a target dose in mice exposed to Mtb aerosol.

SARS-CoV-2 infection associated respiratory disease- COVID-19 has evolved into a pandemic but, being a new form of virus, pathogenesis of disease causation is not fully understood and drugs and vaccines against this virus are still being tested so that no effective drugs or vaccines have been advised by regulatory authority. In this context, the Ministry of AYUSH, Government of India has recommended ‘Ayush Kwath’ to improve the immunity and combat the infection. Our objective of this literature review is to review the role of immunity in pathogenesis of COVID-19 and role of Ayush Kwath against the virus and regulation of immunity. Current review was conducted using a search of available literature on COVID-19 and immunity, Vyadhikshamatwa, Ayurveda and COVID-19, Rasayana, Coronavirus, SARS-CoV-2, immunomodulatory effects of medicinal plants; Tulsi/Holy Basil/Ocimum sanctum, Dalchini/Cinnamon/Cinnamomum zeylanicum, Sunthi/Ginger/Zingiber officinale and Marich/Black Pepper/Piper nigrum. Ayurveda, being an ancient science have both medicinal and cultural values and had stimulated our kitchen and influenced what we ate in different seasons and the remedies we used for common ailments. Herbs such as Tulsi, Marich, Sunthi, Dalchini are the most commonly used and easily available drugs in home. Thus, Ayush Kwath due to its immune-modulatory, antiviral, anti-oxidant, anti-inflammatory, anti-platelet, anti-atherosclerotic, hepato-protective, reno-protective properties; seems to be effective in immuno-regulation for controlling viral infections like COVID-19. Further pre-clinical and clinical trials need to be done for the evaluation of safety and efficacy of this polyherbal formulation.

Background: A new virus of corona family known as novel coronavirus causes coronavirus disease 2019 (COVID-19) also known severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). A good number of principles are found in the classical texts of Ayurveda, which can be compared with the concepts of SARS-CoV-2, and many herbal drugs written in the Ayurvedic text, through its immunomodulatory effect, may enhance host–defense mechanism against such diseases to decrease the mortality. Aim: Our objectives of this review are (i) to understand the concepts of SARS-CoV-2 in light of Ayurveda with their approximate delineation through theoretical analysis; (ii) to review the role of Immune Booster Kashaya Special (IBKS) in boosting and regulating immunity and in preventing complications; and (iii) to explore the effectiveness of each drug among scientific community to facilitate for their extensive research. Methodology: We also searched for relevant keywords in various texts of Ayurveda as well as on online databases such as PubMed, Science Direct, Scopus, CrossRef, and Google Scholar to understand the concepts of SARS-CoV-2 in light of Ayurveda and to explore the possible role of 14 medicinal plants of “immune booster Kashaya” formulation. Result: We found that SARS-CoV-2 is symptomatically very much similar to Sannipataj Jwar as described in Ayurveda and the content of IBKS possesses antiviral, immunomodulatory, antioxidant, antipyretic, anti-inflammatory, cardioprotective, antianxiety, and phagocytic properties. It seems to promote the body's immune mechanism against viral activity and to prevent complications such as inflammation-induced damage and cytokine storming in COVID-19. Conclusion: As there is a lack of an effective SARS-CoV-2 virus-specific medicine or vaccine, these immunomodulatory strategies may be implemented before or shortly after viral exposure and may be paired with antiviral therapies to improve antiviral immune responses by providing interferon-inducing agents or by nonspecific boosting of immunity with innate factors. Immune booster Kashaya should be gone through extensive in vivo and in vitro studies and clinical trials for further validation.

# Background There are various COVID-19 vaccines launched in different parts of the world. As the vaccination drive is increasing, the reports of adverse events following immunization (AEFI) are increasingly reported. Therefore, this research aims to document the adverse events and their determinants following COVID-19 vaccination. # Methods This was a cross-sectional study conducted in a primary healthcare setting of Western Nepal. Those individuals who took the first dose of the ChAdOx1 nCoV-19 vaccine in the health care center (N=425) were eligible for the study. The details to contact the study participants were obtained from the vaccination center. Patients were contacted via phone calls by investigators. Information on demographic details, comorbidities and experiences of any sort of adverse events following vaccination was collected using pre-structured questionnaire. Descriptive statistics was done to describe the categorical variables in frequency and percentage whereas mean, median, standard deviation and interquartile range were calculated for quantitative variables. Binary logistic regression was carried out to explore the potential determinants of AEFI. # Results A total of 302 (71.05%) people were randomly selected from 425 targeted people for vaccination at the primary health care center. A total of 276 (91.3%) people vaccinated with ChAdOx1 nCoV-19 vaccine responded to telephone call. Mean age of participants was 33.63 (± 11.14) years and majority of them were males (54.74%). 91.6% of participants developed some form of AEFI. Among them, 46.6% developed mild AEFI, and 53.4% developed moderate AEFI. Pain on the injection site, generalized weakness, fever, headache, joint and muscle pain, dizziness, and loss of appetite are found to be the “Very common” adverse events. Females tend to develop moderate AEFI than males (OR 2.369; 95% confidence interval, CI=1.398-4.014; *P*=0.001). Age did not seem to be the determinant of AEFI (OR 0.977; CI=0.954-1.002; *P*=0.067). # Conclusions Adverse events following COVID-19 immunization are common but not severe. The severity of AEFI is more in females compared to males. Age did not come out as a predictor for severity of AEFI. Post-vaccination counseling targeting women will improve the acceptance of the vaccine. We recommend further monitoring of AEFI in larger population.

Subclinical hypothyroidism (SCH), is characterized by normal triiodothyronine (T3), tetraiodothyronine (T4) levels and an abnormal increase of serum thyroid stimulating hormone (TSH). The prevalence of hypothyroidism in the developed world is about 4-5% and that of SCH is about 4-15% worldwide and it is increasing at an alarming rate. According to Ayurveda, poor function of Jatharagni and Dhatvagni (digestion and metabolism) produces Ama (advance glycation end products (AGEP) and toxic substances). Ama or AGEP interferes with the function of thyroid gland through interaction with thyroid receptors and causes malfunction of thyroid gland. A female patient of 30 years age, having complaints of weight gain, excessive appetite, fatigue, dry skin, irregular oligo-menorrhea, and constipation along with 21.25 μIU/ml TSH; diagnosed as case of SCH and treated with Trikatu Powder. The contents of Trikatu Powder like; dry ginger, long pepper, and black pepper have shown their beneficial effect on the thyroid gland, and thus are intended to improve thyroid gland function by preventing the development of AGEP and assisting with digestion and metabolism correction. In the present case study, serum TSH level had been reduced to 4.88 μIU/ml, and decreased weight by 8.5 kgs with improvement in all associated symptoms like excessive appetite, hair fall, constipation, dry skin, oligomenorrhea and fatigue with treatment of Trikatu Powder for 4 months. The outcomes suggest that Trikatu powder may be beneficial to reduce serum TSH level, weight and mitigate associated symptoms in patients of SCH.

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection., Introduction The interplay between an individual's genetics and exposure to particular environmental or therapeutic modulators influences mechanisms of disease, prognosis, and treatment. Clinical trials of food allergy tolerance, in which [...]