Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040.

BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.

miRNAs from Inflamed Gingiva Link Gene Signaling to Increased MET Expression.

Several array-based microRNA (miRNA) expression studies independently showed increased expression of miRNAs hsa-miR-130a-3p, -142-3p, -144-3p, -144-5p, -223-3p, -17-5p, and -30e-5p in gingiva affected by periodontal inflammation. We aimed to determine direct target genes and signaling pathways regulated by these miRNAs to identify processes relevant to gingival inflammatory responses and tissue homeostasis. We transfected miRNA mimics (mirVana) for each of the 7 miRNAs separately into human primary gingival fibroblasts cultured from 3 different donors. Following RNA sequencing, differential gene expression and second-generation gene set enrichment analyses were performed. miRNA inhibition and upregulation was validated at the transcript and protein levels using quantitative reverse transcriptase polymerase chain reaction, Western blotting, and reporter gene assays. All 7 miRNAs significantly increased expression of the gene MET proto-oncogene, receptor tyrosine kinase (MET). Expression of known periodontitis risk genes CPEB1, ABCA1, and ATP6V1C1 was significantly repressed by hsa-miR-130a-3p, -144-3p, and -144-5p, respectively. The genes WASL, ENPP5, ARL6IP1, and IDH1 showed the most significant and strongest downregulation after hsa-miR-142-3p, -17-5p, -223-3p, and -30e-5p transfection, respectively. The most significantly regulated gene set of each miRNA related to cell cycle (hsa-miRNA-144-3p and -5p [Padj = 4 × 10-40 and Padj = 4 × 10-6], -miR-17-5p [Padj = 9.5 × 10-23], -miR-30e-5p [Padj = 8.2 × 10-18], -miR-130a-3p [Padj = 5 × 10-15]), integrin cell surface interaction (-miR-223-3p [Padj = 2.4 × 10-7]), and interferon signaling (-miR-142-3p [Padj = 5 × 10-11]). At the end of acute inflammation, gingival miRNAs bring together complex regulatory networks that lead to increased expression of the gene MET. This underscores the importance of mesenchymal cell migration and invasion during gingival tissue remodeling and proliferation in restoring periodontal tissue homeostasis after active inflammation. MET, a receptor of the mitogenic hepatocyte growth factor fibroblast secreted, is a core gene of this process.

Burden of osteoarthritis in India and its states, 1990-2019: findings from the Global Burden of disease study 2019.

OBJECTIVE: To describe the burden of osteoarthritis (OA) in India from 1990 to 2019. DESIGN: Data from Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 were used. The burden of OA -knee OA, hip OA, hand OA, and other OA- was estimated for India and its states from 1990 to 2019 through a systematic analysis of prevalence, incidence, years lived with disability (YLD), and disability-adjusted life years (DALY) using methods reported in GBD 2019 study. RESULT: Around 23.46 million individuals in India had OA in 1990; this increased to 62.35 million in 2019. The age-standardised prevalence of OA increased from 4,895 (95% uncertainty interval (UI):4,420-5,447) in 1990-5313 (95%UI:4,799-5,898) in 2019, per 100,000 persons. Similarly, DALYs due to OA increased from 0.79 million (95%UI:0.40-1.55) to 2.12 million (95%UI:1.07-4.23); while age-standardised DALYs increased from 164 (95%UI:83-325) to 180 (95%UI:91-361) per 100,000 persons from 1990 to 2019. OA was the 20th most common cause of YLDs in India in 2019, accounting for 1.48% (95%UI:0.88-2.78) of all YLDs; increasing from 23rd most common cause in 1990 (1.25%(95%UI:0.74-2.34)). Knee OA was the most common form of OA, followed by hand OA. The prevalence, incidence, and DALYs for OA and knee OA were consistently higher in females than males. CONCLUSION: The burden and impact of OA in India are substantial and is increasing. Adopting suitable control and preventive community measures to reduce modifiable risk factors (obesity, injuries, occupational stress) are needed to reduce the current and future burden of OA in India.

Periodontitis Risk Variants at SIGLEC5 Impair ERG and MAFB Binding.

Periodontitis is a common complex inflammatory disease of the oral cavity. It is characterized by inflammation of gingival tissues and alveolar bone loss. Recently, a genome-wide association study and 2 genome-wide association study meta-analyses found 2 associated regions (haplotype blocks) at the inhibitory immune receptor gene SIGLEC5 to increase the risk for periodontitis. The aims of the current study were the identification of the putative causal variants underlying these associations, characterization of their molecular biological effects, and validation of SIGLEC5 as the target gene. We mapped the associated single-nucleotide polymorphisms to DNA elements with predictive features of regulatory functions and screened the associated alleles for transcription factor (TF) binding sites. Antibody electrophoretic mobility shift assays (EMSAs) with allele-specific probes were used to identify TF binding and to quantify allele-specific effects on binding affinities. Luciferase reporter assays were used to quantify the effect directions and allele-specific strength of the associated regulatory elements. We used CRISPR-dCas9 gene activation to validate SIGLEC5 as a target of the association. EMSA in peripheral blood mononuclear cells showed that E-26 transformation-specific TF-related gene (ERG) binds at rs11084095, with almost complete loss of binding at the minor A-allele. Allele-specific reporter genes showed enhancer function of the DNA sequence at rs11084095, which was abrogated in the background of the A-allele. EMSA in B lymphocytes showed that TF MAF bZIP (MAFB) binds at the common G-allele of rs4284742, whereas the minor A-allele reduced TF binding by 69%, corresponding to 9-fold reduction of luciferase reporter gene activity by the A-allele. Using CRISPR-dCas9, we showed that the enhancer at rs4284742 strongly activated SIGLEC5 expression, validating this gene as the target gene of the association. We conclude that rs11084095 and rs4284742 are putatively causal for the genome-wide significant associations with periodontitis at SIGLEC5 that impair ERG and MAFB binding, respectively.

BACH1 Binding Links the Genetic Risk for Severe Periodontitis with ST8SIA1.

Genome-wide association studies identified various loci associated with periodontal diseases, but assigning causal alleles remains difficult. Likewise, the generation of biological meaning underlying a statistical association has been challenging. Here, we characterized the genetic association at the gene ST8SIA1 that increases the risk for severe periodontitis in smokers. We used CRISPR/dCas9 activation and RNA-sequencing to identify genetic interaction partners of ST8SIA1 and to determine its function in the cell. We used reporter gene assays to identify regulatory elements at the associated single-nucleotide polymorphisms (SNPs) and to determine effect directions and allele-specific changes of enhancer activity. Antibody electrophoretic mobility shift assays proved allele-specific transcription factor binding at the putative causal SNPs. We found the reported periodontitis risk gene ABCA1 as the top upregulated gene following ST8SIA1 activation. Gene set enrichment analysis showed highest effects on integrin cell surface interactions (area under the curve [AUC] = 0.85; q = 4.9 × 10-6) and cell cycle regulation (AUC = 0.89; q = 1.6 × 10-5). We identified 2 associated repressor elements in the introns of ST8SIA1 that bind the transcriptional repressor BACH1. The putative causative variant rs2012722 decreased BACH1 binding by 40%. We also pinpointed ST8SIA1 as the target gene of the association. ST8SIA1 inhibits cell adhesion with extracellular matrix proteins, integrins, and cell cycle, as well as enhances apoptosis. Likewise, tobacco smoke reportedly results in an inhibition of cell adhesion and a decrease in integrin-positive cells and cell growth. We conclude that impaired ST8SIA1 repression, independently caused by reduced BACH1 binding at the effect T allele, as well as by tobacco smoke, contributes to higher ST8SIA1 levels, and in smokers who carry the effect T allele, both factors would be additive with damaging effects on the gingival barrier integrity. The activity of ST8SIA1 is also linked with the periodontitis risk gene ABCA1.

THYROIDITIS DEVELOPING POST INITIATION OF OCTREOTIDE IN A CASE OF TSH SECRETING TUMOR.

Thyroiditis developing post pituitary surgery in a case of TSH secreting tumor has been reported, albeit rarely. A 46 year old female was treated as a case of hypothyroidism for almost five years, however, TSH levels remained unsuppressed in spite of increasing thyroxine doses. A cyclic pattern of TSH with T3 secretion was observed after stopping thyroxine, though T4 levels were normal. T3 suppression test revealed a non suppressed TSH and MRI sella revealed a pituitary mass with Grade 1 cavernous sinus invasion. With a diagnosis of TSH secreting tumor, the patient was initiated on octreotide therapy. TFT normalized within 4 days of initiation of octreotide, tumor size reduced by about 30% within 2 months of therapy and goiter size reduced to almost half with octreotide therapy. Anti TPO levels which were initially negative became positive within a month of octreotide therapy and FNAC thyroid revealed thyroiditis. To the best of our knowledge, this is the second case report of development of thyroiditis after octreotide therapy. The immunomodulatory role of TSH and somatostatin may have a role in the development of thyroiditis in this case.

Parathyroid Adenoma within the Carotid Sheath.

OBJECTIVE: Ectopic parathyroid adenoma is an uncommon cause of primary hyperparathyroidism. Apart from the usually described sites of ectopic parathyroid adenoma, anecdotal case reports of undescended parathyroid adenoma along the carotid artery have been described. METHODS: We report a rare case of a 4 cm large parathyroid adenoma within the carotid sheath. RESULTS: A 27-year-old lady presented with severe bony pains, history of height loss, fracture of left shaft femur following trivial trauma and renal calculi. On evaluation she had hypercalcemia with elevated iPTH suggestive of primary hyperparathyroidism. Ultrasound of neck and 99mTc sestamibi SPECT/CT incorrectly localised the lesion as right inferior parathyroid adenoma leading to a failed initial surgery. Later CECT of the neck identified adenoma posterior to right common carotid artery which was confirmed on repeat surgery and the patient was cured. CONCLUSION: Ectopic parathyroid adenomas are both difficult to localise and are a common cause of failed initial parathyroid surgery. Surgeons should exercise caution while removing a visually normal parathyroid gland. In case of any discordance with the pre-operative localization, a meticulous systematic dissection using the conventional approach should be performed and the possibility of an undescended gland in the carotid sheath should be considered.

Etiology and clinical recommendations to manage the complications following lingual frenectomy: A critical review.

Ankyloglossia, also known as tongue-tie, is an embryological anatomical malformation of the tongue, characterized by an abnormally short and a thick lingual frenum. Tongue-tie restricts the physiologic movements of the tongue and results in various functional, behavioral and speech abnormalities along with the development of frontal and lateral lisps. Ankyloglossia in infants is also linked with the difficulty in breastfeeding difficulty, gagging, choking or vomiting food, delayed development or deterioration of speech and behavioral issues. A lingual frenectomy is a common oral surgical procedure done to correct an ankylosed lingual frenum by severing the abnormal frenal attachment on the ventral surface of the tongue. However, lingual frenectomy is associated with few complications that should be addressed to achieve a good overall prognosis. Though a lot of research is available on the various techniques and rationale to correct ankyloglossia, no paper has yet highlighted the surgical complications associated with lingual frenectomy. Therefore, the present paper for the first time review and highlight the common intraoperative and postoperative complications following lingual frenectomy.

Assessment of plant growth attributes, bioaccumulation, enrichment, and translocation of heavy metals in water lettuce (Pistia stratiotes L.) grown in sugar mill effluent.

This study was conducted to assess the pollutant uptake capability of water lettuce (Pistia stratiotes L.) in terms of bioaccumulation, enrichment, and translocation of heavy metals grown in sugar mill effluent. Results showed that the maximum fresh weight (328.48 ± 2.04 gm kg-1), total chlorophyll content (2.13 ± 2.03 mg g-1 fwt), and relative growth rate, RGR (11.89 gg-1 d-1) of P. stratiotes were observed at 75% concentration of the sugar mill effluent after 60 days of phytoremediation experiment. The bioaccumulation factor (BF) of different heavy metals was greater than 1 with 50% and 75% concentrations of sugar mill effluent and this indicated that P. stratiotes was hyperaccumulator or phytoremediator of these metals. The enrichment factor (EF < 2 for Cu, Fe, Cr, Pb, Zn, and Mn) and (EF > 2 for Cd) indicated that P. stratiotes mineral enrichment deficient and it moderately enriched the different heavy metals. Moreover, translocation factor (TF) was less than 1 which indicated the low mobility of metals in different parts (root and leaves) of P. stratiotes after phytoremediation. Therefore, P. stratiotes can be used for phytotreatment of sugar mill effluent up to 50% to 75% concentrations and considered as hyperaccumulator aquatic plant for different heavy metals and other pollutants from the contaminated effluents.

Assessment of phytokinetic removal of pollutants of paper mill effluent using water hyacinth (Eichhornia crassipes [Mart.] Solms).

Laboratory experiments were carried out to assess the phytoremediation potential of water hyacinth (Eichhornia crassipes [Mart.] Solms) for the removal of different parameters of the paper mill effluent. The maximum removal efficiency of E. crassipes and phytokinetic removal rate were recorded at 50% concentration of the paper mill effluent followed by 60 days of phytoremediation experiments. The most percent reduction was observed in the contents of electrical conductivity (EC; 62.23%), total dissolved solid (TDS; 72.54%), biochemical oxygen demand (BOD; 79.93%), chemical oxygen demand (COD; 85.66%), total Kjeldhal nitrogen (TKN; 89.27%), P (72.39%), Ca2+ (51.79%), Mg2+(51.02%), Na+ (57.10%) and K+(71.47%) and phytokinetic removal rate in the subjects of EC (0.00011 mg l-1d-1), TDS (0.045 mg l-1d-1), BOD (0.0314 mg l-1d-1), COD (0.0461 mg l-1d-1), TKN (0.0034 mg l-1d-1), P (0.0050 mg l-1d-1), Ca2+ (0.0045 mg l-1d-1), Mg2+ (0.003 mg l-1d-1), Na+ (0.004 mg l-1d-1) and K+ (0.004 mg l-1d-1) after phytoremediation at 60 days. The maximum plant height (120.73 cm), fresh plant biomass (383.54 ± 0.15 gkg-1) and total chlorophyll content (3.74 ± 0.05 mgg-1 fwt), crude protein (19.11 mg 100 g-1 fwt), crude fiber (29.92 mg 100 g-1 fwt), total carbohydrate (35.22 mg 100 g-1 fwt) and total ash (26.88 mg 100 g-1 fwt) of E. crassipes were observed with 50% concentration of the paper mill effluent at 60 days of phytoremediation experiments. The maximum relative growth rate (13.86 gg-1 d-1) of E. crassipes was detected with 50% concentration of paper mill effluent at 60 days of phytoremediation experiments. Therefore, E. crassipes was recorded to be feasible for the removal of different pollutants of paper mill effluent, responsible for the eutrophication of the aquatic resources.

Comparative reliability and diagnostic performance of conventional 3T magnetic resonance imaging and 1.5T magnetic resonance arthrography for the evaluation of internal derangement of the hip.

OBJECTIVE: To compare the diagnostic accuracy of conventional 3T MRI against 1.5T MR arthrography (MRA) in patients with clinical femoroacetabular impingement (FAI). METHODS: Sixty-eight consecutive patients with clinical FAI underwent both 1.5T MRA and 3T MRI. Imaging was prospectively analysed by two musculoskeletal radiologists, blinded to patient outcomes and scored for internal derangement including labral and cartilage abnormality. Interobserver variation was assessed by kappa analysis. Thirty-nine patients subsequently underwent hip arthroscopy and surgical results and radiology findings were analysed. RESULTS: Both readers had higher sensitivities for detecting labral tears with 3T MRI compared to 1.5T MRA (not statistically significant p=0.07). For acetabular cartilage defect both readers had higher statistically significant sensitivities using 3T MRI compared to 1.5T MRA (p=0.02). Both readers had a slightly higher sensitivity for detecting delamination with 1.5T MRA compared to 3T MRI, but these differences were not statistically significant (p=0.66). Interobserver agreement was substantial to perfect agreement for all parameters except the identification of delamination (3T MRI showed moderate agreement and 1.5T MRA substantial agreement). CONCLUSION: Conventional 3T MRI may be at least equivalent to 1.5T MRA in detecting acetabular labrum and possibly superior to 1.5T MRA in detecting cartilage defects in patients with suspected FAI. KEY POINTS: • Conventional 3T MRI is equivalent to 1.5T MRA for diagnosing labral tears. • Conventional 3T MRI is superior to 1.5T MRA for diagnosing acetabular cartilage defect. • Conventional 3T MRI is equivalent to 1.5T MRA for diagnosing cartilage delamination. • Symptom severity score was significantly higher (p<0.05) in group proceeding to surgery.

Phytoremediation potential of water caltrop (Trapa natans L.) using municipal wastewater of the activated sludge process-based municipal wastewater treatment plant.

Phytoremediation experiments were carried out to assess the phytoremediation potential of water caltrop (Trapa natans L.) using municipal wastewater collected from the activated sludge process- (ASP) based municipal wastewater treatment plant. The results revealed that T. natans significantly (P ≤ .05/P ≤ .01/P ≤ .001) reduced the contents of total dissolved solids (TDS), electrical conductivity (EC), biochemical oxygen demand (BOD5), chemical oxygen demand, total Kjeldahl nitrogen, phosphate ([Formula: see text]), sodium (Na+), potassium (K+), calcium (Ca2+), magnesium (Mg2+), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), lead (Pb), zinc (Zn), standard plate count, and most probable number of the municipal wastewater after phytoremediation experiments. The maximum removal of these parameters was obtained at 60 days of the phytoremediation experiments, but the removal rate of these parameters was gradually increased from 15 to 45 days and it was slightly decreased at 60 days. Most contents of Cd, Cu, Fe, Mn and Zn were translocated in the leaves of T. natans, whereas most contents of Cr and Pb were accumulated in the root of T. natans after phytoremediation experiments. The contents of different biochemical components were recorded in the order of total sugar > crude protein > total ash > crude fiber > total fat in T. natans after phytoremediation of municipal wastewater. Therefore, T. natans was found to be effective for the removal of different parameters of municipal wastewater and can be used effectively to reduce the pollution load of municipal wastewater drained from the ASP-based treatment plants.

The BiPo-3 detector.

The BiPo-3 detector is a low radioactive detector dedicated to measuring ultra-low natural contaminations of 208Tl and 214Bi in thin materials, initially developed to measure the radiopurity of the double ß decay source foils of the SuperNEMO experiment at the µBq/kg level. The BiPo-3 technique consists in installing the foil of interest between two thin ultra-radiopure scintillators coupled to low radioactive photomultipliers. The design and performances of the detector are presented. In this paper, the final results of the 208Tl and 214Bi activity measurements of the first enriched 82Se foils are reported for the first time, showing the capability of the detector to reach sensitivities in the range of some µBq/kg.

Association of heat stress protein 90 and 70 gene polymorphism with adaptability traits in Indian sheep (Ovis aries).

Heat stress proteins assist cellular proteins in the acquisition of native structure. The present research was conducted to study how thermo-tolerance is modulated by HSP90 and HSP70 gene polymorphism and its association with hemato-physio-biochemical parameters, supported by their expression profiles in Chokla, Magra, Marwari, and Madras Red sheep breeds. Least square analysis revealed significant effect (P < 0.05) of season and breed on all the physiological parameters, i.e., temperature, respiratory rate, and pulse rate (a.m. and p.m.), as well as hematological parameters like Hb, packed cell volume, total erythrocyte count (TEC), neutrophil/lymphocyte (N/L) ratio, and total leukocyte count (TLC). There was a significant influence (P < 0.05) of breed on biochemical parameters such as glucose, SGOT, phosphorous, triglyceride, and cholesterol. Eight fragments were amplified and sequenced in HSP90, and 70 genes and 13 single-nucleotide polymorphisms (SNPs) were identified. Tetra-primer amplification refractory mutation system PCR, PCR-RFLP, and allele-specific PCR genotyping protocols were developed for large-scale genotyping of five SNPs. A significant difference (P < 0.05) of rectal temperature (a.m.), respiratory rate (p.m.), triglyceride, and total protein was observed at SNP01; albumin at SNP2; pulse rate (p.m.) at SNP3; and rectal temperature (p.m.), pulse rate (p.m.), Hb (g/dL), and N/L ratio at SNP4 and TLC at SNP5. Gene expression analysis revealed higher expression in less adapted animals with Madras Red < Magra < Chokla < Marwari expression pattern [corrected]. Predominant allele was found to be superior in most of the SNPs (SNP1-4) indicating the selection acting in directional manner (positive selection). Finally, it is concluded that TACCA haplotype combination of SNP1-SNP2-SNP3-SNP4-SNP5 might be of some selection advantage for the identification of animals more adaptable to heat stress.

Search for Neutrinoless Quadruple-ß Decay of

We report the results of a first experimental search for lepton number violation by four units in the neutrinoless quadruple-ß decay of ^{150}Nd using a total exposure of 0.19 kg yr recorded with the NEMO-3 detector at the Modane Underground Laboratory. We find no evidence of this decay and set lower limits on the half-life in the range T_{1/2}>(1.1-3.2)×10^{21} yr at the 90% C.L., depending on the model used for the kinematic distributions of the emitted electrons.