Treatment challenges and outcomes of older patients with acute myeloid leukemia from India.

Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137-234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.

Injury to the Submandibular Duct and Secondary Fibrosis Causing Sialocele: An Unusual Complication of Submental Intubation.

Maxillofacial fractures with the nasal/skull base fractures may preclude nasotracheal intubation, and oro-tracheal intubation may obstruct surgical access. In these cases, submental intubation is a safe and well-accepted alternative, associated with low morbidity and complication rate. We report a case of one such rare complication, wherein following submental intubation, the patient presented with a sublingual sialocele, associated with dilatation of the submandibular duct with surrounding fibrosis. The secondary sublingual sialocele we encountered could have been due to errors in the technique of submental intubation. Hence, thorough knowledge of the submental and submandibular region's anatomy is important to avoid complications.

Mixed Epithelial Stromal Tumor of the Kidney With a Mesenteric Lymph Node: A Case Report and Literature Review.

Mixed epithelial and stromal tumor (MEST) of the kidney belongs to the broad spectrum of renal neoplasms, distinguished by their varying composition of stromal to epithelial components. The histopathological display of the biphasic growth pattern of mesenchymal and epithelial elements, often with estrogen and progesterone receptor positivity, clinches the diagnosis. It is typically benign, with low recurrence rates and excellent prognosis after surgical resection. MEST constitutes a rare and unique subset, with limited research and understanding, requiring differentiation from other renal tumors. Our patient's presentation of a morphologically benign renal MEST with an imaging-positive inferior mesenteric lymph node renders this case exceptionally rare.

NLRP12 downregulates the Wnt/ß-catenin pathway via interaction with STK38 to suppress colorectal cancer.

Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/ß-catenin pathway, but not NF-κB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates ß-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of ß-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3ß, leading to the degradation of ß-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3ß and ß-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/ß-catenin pathway, and the NLRP12/STK38/GSK3ß signaling axis could be a promising therapeutic target for CRC.

Critical role of antioxidant programs in enzalutamide-resistant prostate cancer.

Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.

DISTRIBUTION OF RADIONUCLIDES IN RIVER SEDIMENTS OF KATHMANDU VALLEY, NEPAL AND THE EVALUATION OF ASSOCIATED RADIATION HAZARD.

The natural radioactivity in our living environment is mainly due to radionuclides of 40K, 232Th and 238U. We studied the distribution of these radionuclides in the sediment of different rivers and streams throughout the Kathmandu valley. The activity concentrations were determined by using digiBase NaI(TI) gamma-ray spectrometer, and further they were used to calculate radiological hazard indices to estimate the risk associated with the use of these sediments. The average activity concentrations for 40K, 232Th and 238U were found to be 378.54 ± 109.06, 45.95 ± 18.47 and 26.90 ± 9.61 Bq per kg, respectively. The average concentrations and calculated hazard indices have been compared with the respective reported activity concentration in different countries. This study reveals that there is no radiological threat using these local sediments as building materials and for other purposes.

Block Copolymer-Assisted Synthesis of Iron Oxide Nanoparticles for Effective Removal of Congo Red.

Iron oxide nanoparticles (IONPs) were synthesized via a block copolymer-assisted hydrothermal method and the phase purity and the crystal structure were investigated by X-ray diffraction. The Rietveld analysis of X-ray diffractometer spectra shows the hexagonal phase symmetry of α-Fe2O3. Further, the vibrational study suggests Raman active modes: 2A1g + 5Eg associated with α-Fe2O3, which corroborates the Rietveld analysis and orbital analysis of 2PFe. The superparamagnetic behavior is confirmed by magnetic measurements performed by the physical properties measurement system. The systematic study of the Congo red (CR) interaction with IONPs using a UV-visible spectrophotometer and a liquid chromatography-tandem mass spectrometry system equipped with a triple quadrupole mass analyzer and an electrospray ionization interface shows effective adsorption. In visible light, the Fe2O3 nanoparticles get easily excited and generate electrons and holes. The photogenerated electrons reduce the Fe3+ ions to Fe2+ ions. The Fe2+/H2O2 oxidizes CR by the Fenton mechanism. The strong adsorption ability of prepared nanoparticles towards dyes attributes the potential candidates for wastewater treatment and other catalytic applications.

Towards precision radiation oncology: endocrine therapy response as a biomarker for personalization of breast radiotherapy.

Targeted therapies, such as endocrine therapies (ET), can exert selective pressure on cancer cells and promote adaptations that confer treatment resistance. In this study, we show that ET resistance in breast cancer drives radiation resistance through reprogramming of DNA repair pathways. We also show that pharmacological bromodomain and extraterminal domain inhibition reverses pathological DNA repair reprogramming in ET-resistant breast tumors and overcomes resistance to radiation therapy.

Central Skull Base Osteomyelitis: Multimodality Imaging and Clinical Findings from a Large Indian Cohort.

Background: Central or atypical skull base osteomyelitis (CSBO) often presents with severe unrelenting headache and progressive mono or polyneuritis cranialis. MRI and CT are used as initial imaging techniques but have a poor specificity and sensitivity. Objective: To analyze our cohort of CSBO. Materials and Methods: Over a 5-year period [2015-2020], we retrospectively analyzed the records of all patients with CSBO who had undergone a 3T MRI Brain, MR angiography, regional FDG PET-CT, and skeletal scintigraphy with 99mTc MDP/SPECT-CT. Surgical biopsy specimens were sent for bacterial and fungal cultures. Results: In total, 17 patients with CSBO were identified. Typically, 88% of patients presented with severe unilateral headache. All patients had at least a cranial mono or polyneuritis. The majority of patients were diabetic [64%]. MRI was normal in 42% of patients, whereas PET-CT and with 99mTc MDP scan and SPECT-CT were abnormal in all patients. Conclusion: Our series of CSBO showed a 40% mortality rate with significant morbidity and relentless progression. Patients required repeated PET CT and bone scans to detect regression of disease activity. The average duration of IV therapy ranged from 3 weeks to 9 months and oral therapy for around 2-3 months. Cure was defined after taking into account the original diagnosis, symptom resolution, and concordant reduction of tissue uptake on PET CT and 99mTc bone scan. The combination of MRI, FDG PET CT, and 99mTc bone scan with concurrent SPECT CT was able to detect disease and disease progression in all patients.

Prostate Cancer Transcriptomic Regulation by the Interplay of Germline Risk Alleles, Somatic Mutations, and 3D Genomic Architecture.

Prostate cancer is one of the most heritable human cancers. Genome-wide association studies have identified at least 185 prostate cancer germline risk alleles, most noncoding. We used integrative three-dimensional (3D) spatial genomics to identify the chromatin interaction targets of 45 prostate cancer risk alleles, 31 of which were associated with the transcriptional regulation of target genes in 565 localized prostate tumors. To supplement these 31, we verified transcriptional targets for 56 additional risk alleles using linear proximity and linkage disequilibrium analysis in localized prostate tumors. Some individual risk alleles influenced multiple target genes; others specifically influenced only distal genes while leaving proximal ones unaffected. Several risk alleles exhibited widespread germline-somatic interactions in transcriptional regulation, having different effects in tumors with loss of PTEN or RB1 relative to those without. These data clarify functional prostate cancer risk alleles in large linkage blocks and outline a strategy to model multidimensional transcriptional regulation. SIGNIFICANCE: Many prostate cancer germline risk alleles are enriched in the noncoding regions of the genome and are hypothesized to regulate transcription. We present a 3D genomics framework to unravel risk SNP function and describe the widespread germline-somatic interplay in transcription control. This article is highlighted in the In This Issue feature, p. 2711.

Targeting ESR1 mutation-induced transcriptional addiction in breast cancer with BET inhibition.

Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1,200 Federal Drug Administration-approved (FDA-approved) drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib + fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with WT cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.

FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity.

FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2's role in EC is incompletely understood. Functional investigations using human and mouse EC cell lines revealed that FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. In live animals, conditional inactivation of Foxa2 or Pten alone in endometrial epithelium did not result in ECs, but simultaneous inactivation of both genes resulted in lethal ECs with complete penetrance, establishing potent synergism between Foxa2 and PI3K signaling. Studies in tumor-derived cell lines and organoids highlighted additional invasion and cell growth phenotypes associated with malignant transformation and identified key mediators, including Myc and Cdh1. Transcriptome and cistrome analyses revealed that FOXA2 broadly controls gene expression programs through modification of enhancer activity in addition to regulating specific target genes, rationalizing its tumor suppressor functions. By integrating results from our cell lines, organoids, animal models, and patient data, our findings demonstrated that FOXA2 is an endometrial tumor suppressor associated with aggressive disease and with shared commonalities among its roles in endometrial function and carcinogenesis.

Targeting radioresistance and replication fork stability in prostate cancer.

The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC). We hypothesized novel combinatorial strategies are likely to enhance the efficacy of BETi. By using PCa patient-derived explants and xenograft models, we show that BETi treatment enhanced the efficacy of radiation therapy (RT) and overcame radioresistance. Mechanistically, BETi potentiated the activity of RT by blocking DNA repair. We also report a synergistic relationship between BETi and topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi OTX015 synergized with the new class of synthetic noncamptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiated the antitumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer to CRPC. TOP1 was highly expressed in metastatic CRPC, and its expression correlated with the expression of BET family genes. These studies open new avenues for the rational combinatorial treatment of aggressive PCa.

A composite polyphenol-rich extract improved growth performance, ruminal fermentation and immunity, while decreasing methanogenesis and excretion of nitrogen and phosphorus in growing buffaloes.

The effects of a composite polyphenolic-rich extract (CPRE) on ruminal fermentation, nutrient utilisation, growth performance, excretion of nitrogen and phosphorus and methane emission were studied in growing buffaloes. Four herbal dry extracts prepared from Acacia arabica (babul; bark), Acacia catechu (cutch; bark), Punica granatum (pomegranate; peel) and Eugenia jambolana (Indian blackberry; seeds) were mixed in an equal proportion (1:1:1:1) to prepare the CPRE that contained mainly phenolic compounds (146 g/kg), flavonoids (41.7 g/kg) and saponins (40.5 g/kg). First, in vitro tests were performed for ruminal fermentation and feed degradability using ruminal fluid as inocula and CPRE at 0 to 40 g/kg substrate to decide an optimal dose of CPRE for an in vivo study on buffaloes. In the animal study, 20 buffaloes were randomly assigned to two groups (n = 10)-a control diet and a CPRE diet (control diet added with extra 20 g/kg of CPRE). The in vitro tests suggested that addition of CPRE at 20 g/kg substrate increased degradability of substrate, short-chain fatty acid concentration and propionate proportion, and reduced methane production, acetate proportion, acetate:propionate ratio and ammonia concentration in fermentation media, which were also noted in the rumen of buffaloes. Feeding CRPE to buffaloes did not affect feed intake, but increased daily body weight gain, dry matter and crude protein digestibility and nitrogen and phosphorus retention in the body. Total bacteria, methanogens and protozoal numbers were similar between two groups, but Fibrobacter succinogenes increased in the rumen of buffaloes fed CPRE. Concentrations of total, essential, non-essential and glucogenic amino acids were greater in the plasma of CPRE-fed buffaloes. Cell-mediated immune response improved in the CPRE-fed buffaloes compared with the control group. Estimated methane production and excretion of nitrogen and phosphorus per unit of body weight gain decreased in the CPRE group. The comprehensive results of this study clearly suggested that the composite polyphenol-rich feed additive at 20 g/kg diet improved growth performance, ruminal fermentation, immunity and plasma amino acids profile, whereas it reduced indicators of environmental impacts of buffalo production.

Associations between breast implants and postpartum lactational mastitis in breastfeeding women: retrospective study.

OBJECTIVE: To examine the putative associations between breast implants and postpartum lactational mastitis. DESIGN: Observational retrospective study. SETTING: Digital database of Maccabi Healthcare Services, integrated health maintenance organisation in Israel. POPULATION: Breastfeeding mothers from 2003 to 2016 based on an initial health maintenance organisation data set of 28 383 singleton live births in Israel. METHODS: Multivariate analysis and propensity score matching were used to test the extent to which breast implants were associated with lactational mastitis during the 6-month postpartum period in breastfeeding mothers. Analyses for potential confounders were adjusted for socio-economic status, smoking and parity. MAIN OUTCOME MEASURE: Lactational mastitis among breastfeeding women with breast implants compared with women without breast implants. RESULTS: Mothers with breast implants (n = 6099) were significantly (P < 0.001) more likely to be diagnosed with postpartum mastitis (8.3%) than mothers with no breast implants(n = 22 284) (6.6%) at an odds ratio of 1.22 (95% CI 1.09-1.35) after adjusting for confounders. CONCLUSION: Breast augmentation is associated with an increased risk of postpartum lactational mastitis in the 6-month postpartum period. In light of these findings, it is important for health professionals to instruct women who have undergone breast augmentation on correct breastfeeding techniques, ways to avoid risk factors, and to be alert to signs permitting the early detection of lactational mastitis. TWEETABLE ABSTRACT: A study of over 28,000 breastfeeding women has shown that breast augmentation is associated with an increased risk of postpartum lactational mastitis in the six-month postpartum period.

Prevalence of hypertension and its associated risk factors in Dharwad population: A cross-sectional study.

The study aims to determine the prevalence of hypertension and associated risk factors. The study includes 9754 participants, out of which 6403 were found to be associated with hypertension. Among 6403 participants 27.75% were newly diagnosed with hypertension during examination. The present study showed, age as one of the significant risk factors for prevalence of hypertension. Further observations revealed that, the prevalence of hypertension was higher in alcohol-intake, tobacco-smoking/chewing participants and sedentary life style is also one of significant risk factor for hypertension. Overall increased rate of hypertension pose a biggest challenge for health sector in Dharwad district.

Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.

Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene under the control of a human Synapsin promoter. We first demonstrated that intracerebroventricular (ICV) injection of this vector in wild-type mice on postnatal day 10 (P10) results in increases in ouabain-sensitive ATPase activity and in expression of reporter genes in targeted brain regions. We then tested this vector in mutant mice. Simultaneous intracisterna magna and bilateral ICV injections of this vector at P10 resulted, at P40, in reduction of inducible hemiplegia spells, improvement in balance beam test performance, and prolonged survival of treated mutant mice up to P70. Our study demonstrates, as a proof of concept, that gene therapy can induce favorable effects in a disease caused by a mutation of the gene of a protein that is, at the same time, an ATPase enzyme, a pump, and a signal transduction factor.

Prostate carcinogenesis: inflammatory storms.

Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.