IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy.

PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well-tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action. EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models and primary PDX tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy. RESULTS: IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44% respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2 targeted monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates. CONCLUSIONS: These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.

Taxonomy and feeding of Forcipomyia (Microhelea) fuliginosa Meigen and Forcipomyia (Microhelea) esakiana Tokunaga (Diptera: Ceratopogonidae) on Antheraea mylitta Drury (Lepidoptera: Saturniidae).

Taxonomic equivocality and complexity exist in the two species of Ceratopogonids, Forcipomyia (Microhelea) fuliginosa Meigen and Forcipomyia (Microhelea) esakiana Tokunaga. Incongruencies and inaccuracies in species identification restrict further biological and ecological studies on the host-ectoparasite association. Preferential landing and hemolymphophagy of F. fuliginosa and F. esakiana on Antheraea mylitta Drury larva were studied under field conditions. The silkworm A. mylitta is reared in the tasar sericulture industry, contributing 1466 metric tons (202122) of indigenous raw silk in India. Ectoparasitic behavior of the biting midges, F. fuliginosa, and F. esakiana is an increasing threat to the silkworm, necessitating proper identification. Intra and inter-variations of these two closely related species have been stated. Morphological-based identification of these species has been substantiated with COX1 molecular data. A Bayesian-modeled approach to reconstruct the dendrogram of the two species based on the COX1 sequences generated has been presented along with the referred sequences of F. fuliginosa from Genebank. The species F. esakiana is being reported for the first time from India, along with its ectoparasitic hemolymphophagous nature. The role of these insectivorous species in transmitting pathogens to the larvae of tasar silk needs further investigation.

The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth.

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target for TNBC. METHODS: The mRNA expression levels of NUDT5 in breast cancers were investigated using TCGA and METABRIC (Curtis) datasets. NUDT5 ablation was achieved through siRNA targeting and NUDT5 inhibition with the small molecule inhibitor TH5427. Xenograft TNBC animal models were employed to assess the effect of NUDT5 inhibition on in vivo tumor growth. Proliferation, death, and DNA replication assays were conducted to investigate the cellular biological effects of NUDT5 loss or inhibition. The accumulation of 8-oxo-guanine (8-oxoG) and the induction of γH2AX after NUDT5 loss was determined by immunofluorescence staining. The impact of NUDT5 loss on replication fork was assessed by measuring DNA fiber length. RESULTS: In this study, we demonstrated the significant role of an overexpressed phosphatase, NUDT5, in regulating oxidative DNA damage in TNBCs. Our findings indicate that loss of NUDT5 results in suppressed growth of TNBC both in vitro and in vivo. This growth inhibition is not attributed to cell death, but rather to the suppression of proliferation. The loss or inhibition of NUDT5 led to an increase in the oxidative DNA lesion 8-oxoG, and triggered the DNA damage response in the nucleus. The interference with DNA replication ultimately inhibited proliferation. CONCLUSIONS: NUDT5 plays a crucial role in preventing oxidative DNA damage in TNBC cells. The loss or inhibition of NUDT5 significantly suppresses the growth of TNBCs. These biological and mechanistic studies provide the groundwork for future research and the potential development of NUDT5 inhibitors as a promising therapeutic approach for TNBC patients.

Effect of substrate salinity and pH on life history traits of the bluetongue virus vector Culicoides peregrinus.

Habitat selection of Culicoides spp. (Diptera: Ceratopogonidae) is influenced by the physicochemical factors such as temperature, pH, salinity, moisture, conductivity, organic and inorganic compounds of substrates. These factors determine the life history traits of the vectors. We studied the influence of substrate salinity (0-40 parts per thousand, ppt) and pH (pH 1-13) on oviposition, egg hatching, larval survivability, and adult emergence of Culicoides peregrinus Kieffer under laboratory conditions. Most eggs (80.74%) were laid in 0 ppt and 95% in pH 7 but lowered with increased salinity and pH levels. It was observed that the females did not lay eggs in 30 ppt to 40 ppt salinity; pH 1 and pH 13 but interestingly up to 95% of the eggs were retained within the abdomen. Little effect of salinity and pH on egg hatching was observed up to 5 ppt and 10 ppt except at the extreme values of 40 ppt and pH 1, pH 13. Pupation did not occur in rearing plates with high salinities, 30 ppt and 40 ppt, although the few eggs hatched when exposed to such salinity. In low salinity (0 to 2 ppt), occurrence of adult emergence was more and then decreased with increasing salinity. Maximum emergence was seen when the rearing media was alkaline. This study deals with the suitability of breeding substrate of C. peregrinus when exposed to salinity and pH ranges. Our study suggests the ambient salinity and pH ranges to be maintained during laboratory rearing of this vector species.

A taxonomic revision of the Indian species of the 'Aterinervis' group of Culicoides Latreille Subgenus Hoffmania Fox (Diptera: Ceratopogonidae).

The seven species of Culicoides spp. belonging to the Aterinervis Group of subgenus Hoffmania Fox reported from India are revised. The study is based on type material and fresh specimens trapped during the Annual Biodiversity Assessment (2nd & 4th) of Neora Valley National Park (NVNP) in the Darjeeling-Sikkim Himalaya of India. Comparative redescriptions of adult male and female of Culicoides isoregalis, C. neoregalis, C. pararegalis, C. pseudoregalis, C. quasiregalis, C. regalis and C. subregalis are provided along with the formal transfer of the nominate species, Culicoides aterinervis from subgenus Culicoides Latreille to Hoffmania. A key to the Indian species belonging to the Aterinervis group is provided along with a list of the Culicoides species present in the Darjeeling-Sikkim Himalayas.

In vitro biochemical characterization and identification of hemolytic bacteria associated with life history of Culicoides peregrinus (Diptera: Ceratopogonidae), a vector of bluetongue virus.

Gut bacterial communities in insects provide several beneficial roles like nutrition, digestion, fecundity, and survival of the host. The microbial communities of Culicoides spp. (Diptera: Ceratopogonidae) vary with parity, developmental stages, and environmental factors. Previous studies have revealed the presence of hemolytic bacteria in adult Culicoides peregrinus Kieffer (Diptera: Ceratopogonidae), an important vector of bluetongue virus (BTV). Our objectives were (i) to identify bacterial communities with hemolytic activities associated with all life stages and (ii) to compare between reared and field-collected adults including age graded females. Bacterial identification followed Sanger sequencing of 16S rRNA. In vitro biochemical characterizations including antibiotic sensitivity tests were also done. The majority of bacterial species were beta hemolytic with one, Alcaligenes faecalis, showing alpha hemolysis. Most bacterial species were observed in field-collected adults except Proteus spp. Throughout the life history of the vector, Bacillus cereus (CU6A, CU1E) and Paenibacillus sp. (CU9G) were detected indicating their possible role in blood digestion within the gut of this vector species. In vivo hemolytic activities of these culturable bacterial communities within this vector may be addressed in future. These hemolytic bacterial communities may be targeted to develop novel and effective strategies for vector control.

Molecular identification of Culicoides oxystoma and Culicoides actoni vectors of bluetongue virus.

Bluetongue is a non-contagious viral disease causing significant economic losses throughout the world. The bluetongue vectors Culicoides oxystoma and Culicoides actoni, which play a significant role in the transmission of various pathogens, are distributed across different geographical realms. Adults are minute in size with wide phenotypic variation, so morphology-based species identification is severely constrained by preparatory time and shortage of taxonomic expertise. To make the identification process rapid and effective, a specific primer was designed for the identification of C. actoni based on the multiple sequence alignment of ITS1 sequences of 11 Culicoides species. Along with this, a refined version of existing C. oxystoma specific primer was proposed. The primer sets distinguished C. oxystoma and C. actoni from a pooled sample consisting of other Culicoides species as well as closely related genera such as Forcipomyia and Alluaudomyia. Our findings suggest that the primers were species specific, sensitive and have potential to discriminate vector species C. oxystoma and C. actoni from pooled samples. To the best of our knowledge, these are the first ITS1 sequences generated and submitted in GenBank for Culicoides innoxius, Culicoides shortti, Culicoides palpifer and Culicoides anophelis and the first for Culicoides peregrinus, Culicoides fulvus and C. actoni from India.

A Metagenomic Based Approach on Abundance and Diversity of Bacterial Communities Across the Life Stages of Culicoides peregrinus (Diptera: Ceratopogonidae) a Vector of Bluetongue Virus.

During larval rearing of Culicoides peregrinus Kieffer (Diptera: Ceratopogonidae) it was obligatory to add a small quantity of mud from larval habitat to nutrient broth in culture plates. This initiated microbial growth in rearing plates which facilitated growth and development of immature. The primary aim was to enumerate gut microbial communities across the different life stages of C. peregrinus. Amplicon sequencing of the V3-V4 hypervariable region (16S rDNA) was done on Illumina Miseq platform to detect gut bacterial communities at different life stages, while ITS regions (18S rRNA) were targeted for fungal communities of the 4th instar larvae. The major findings were: 1) Phylum Proteobacteria and Firmicutes were the most abundant throughout the life stages, along with the highest bacterial alpha diversity in the egg, 2) bacterial compositions were similar to laboratory reared and field collected adults, and 3) abundant fungal phyla associated with the larval gut were Ascomycota and Basidiomycota. Furthermore, analyses of the gut microbiome with METAGENassist might be indicative of their likely function in the natural habitat. Abundant gut-associated bacteria and/or fungal genera detected in the present study could be used as dietary supplements to establish laboratory colonies for further vectorial research. While, individual roles of the bacteria or fungi in paratransgenesis are warned for their possible utilization to frame the management strategy in upcoming works.

Host preference of bluetongue virus vectors, Culicoides species associated with livestock in West Bengal, India: Potential relevance on bluetongue epidemiology.

Determination of host choice of Culicoides species (Diptera: Ceratopogonidae), the vectors of bluetongue virus (BTV), is pivotal to ascertain the role of each species in the transmission of pathogens, pest management and enumeration of disease prediction models. Host preference of livestock associated Culicoides midges was investigated in West Bengal, India with four replicates of a 3 × 3 Latin square design during August and September 2021. Adult Culicoides were mouth aspirated from three BTV hosts viz., cattle, sheep and goats. Mouth aspirating was validated by the sweep net collections. The host-baited collections recorded seven Culicoides species; with the highest landing rate on cattle (n = 5,667; 92.9%) followed by sheep (n = 365; 6.0%) and goat (n = 67; 1.1%). Based on the Jacob's selectivity index, all midge species, except for Culicoides fulvus Sen & Das Gupta, encountered, preferred cattle over other mammalian hosts. Culicoides oxystoma Kieffer, the subgenus Trithecoides Wirth & Hubert and Culicoides actoni Smith, predominated on the ventral region (belly/flank) of the cattle. However, Culicoides peregrinus Kieffer and C. actoni were observed to be prevalent in the leg region of sheep. A significantly higher percentage of female (99.9%) with only 0.3% of male were trapped in aspiration based animal baited collections. On the other hand sweep net and light trap catch comprises of 50.7%, 89.7% female and 49.2%, 10.2% male respectively. Surprisingly, DNA based blood meal analysis revealed human blood from the midges trapped in UV-LED light traps. Supplying the first evidence that Culicoides similis Carter, Ingram & Macfie, C. fulvus and Culicoides palpifer Das Gupta & Ghosh, feed on humans.

Targeting the mTOR Pathway for the Prevention of ER-Negative Breast Cancer.

PREVENTION RELEVANCE: Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787.

Evaluation of resting traps: An approach to understand resting biology of Culicoides spp. in backyard cattle shed.

Worldwide Culicoides biting midges transmit disease-causing agents that have significant economic impact on livestock industries. The aim of this study was to evaluate the sticky resting box traps to elucidate the resting behaviour of adult Culicoides in backyard cattle shed. Four different experiments were conducted over a six-month period based on types of resting box traps (material, colour, texture & height). During the study period 8870 individuals comprising 4046 (45.61%) males and 4824 (54.39%) females were collected. During the study period no significant preference was observed for the choice of resting box material (plywood & carton). For the colour experiment: adult Culicoides were retrieved from black box trap the most (21.15%) followed by blue (19.93%), red (17.84%), pink (14.06%), green (13.31%), yellow (7.21%) and the white (6.51%). Differential catch in the trap with surface texture (rough & smooth) was statistically significant (χ2 = 4.09, df = 1, P < 0.05). The highest proportion of males (n=987, 0.64) was recovered in the lower sticky resting box while the highest proportion of females (n=1318, 0.64) was collected in the upper sticky resting box during the study period. Sticky Resting Box (SRB) seems to be an effective tool for passive monitoring of resting adult vectors of Culicoides spp. prevalent in backyard sheds of West Bengal, India.

Blood meal analysis of Culicoides species associated with livestock in West Bengal, India.

Knowledge gaps exist on the feeding pattern and host range of bluetongue virus vectors, Culicoides species, associated with livestock in India. Adult midges were trapped with ultraviolet light traps at 13 household farms adjacent to human biotope. Host DNA was isolated from individual females (n = 101; blood engorged-82, gravid-4 and parous-15) and subjected to PCR amplification targeting CytB and 16S rRNA gene fragments followed by sequencing of amplified DNA samples. However, DNA sequences from only 71 individuals (70.3%) comprising of 10 Culicoides species were obtained. Blood meal analysis revealed at least 10 species that fed on five mammalian hosts including humans, but surprisingly none tested positive for birds. Results revealed that Culicoides innoxius tested positive for four not previously recognized species indicating a potential role as a vector species. Likewise, Culicoides shortti and Culicoides hegneri preferred goat and cattle respectively as hosts, whereas Culicoides palpifer preferred cattle along with buffalo as hosts, which is being reported for the first time. This is the first document on DNA-based blood meal identification and feeding preference of Culicoides midges associated with livestock in India.

SOX9 Is Essential for Triple-Negative Breast Cancer Cell Survival and Metastasis.

Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and lacks effective targeted treatment strategies. Previously, we identified 33 transcription factors highly expressed in TNBC. Here, we focused on six sex determining region Y-related HMG-box (SOX) transcription factors (SOX4, 6, 8, 9, 10, and 11) highly expressed in TNBCs. Our siRNA screening assay demonstrated that SOX9 knockdown suppressed TNBC cell growth and invasion in vitro. Thus, we hypothesized that SOX9 is an important regulator of breast cancer survival and metastasis, and demonstrated that knockout of SOX9 reduced breast tumor growth and lung metastasis in vivo. In addition, we found that loss of SOX9 induced profound apoptosis, with only a slight impairment of G1 to S progression within the cell cycle, and that SOX9 directly regulates genes controlling apoptosis. On the basis of published CHIP-seq data, we demonstrated that SOX9 binds to the promoter of apoptosis-regulating genes (tnfrsf1b, fadd, tnfrsf10a, tnfrsf10b, and ripk1), and represses their expression. SOX9 knockdown upregulates these genes, consistent with the induction of apoptosis. Analysis of available CHIP-seq data showed that SOX9 binds to the promoters of several epithelial-mesenchymal transition (EMT)- and metastasis-regulating genes. Using CHIP assays, we demonstrated that SOX9 directly binds the promoters of genes involved in EMT (vim, cldn1, ctnnb1, and zeb1) and that SOX9 knockdown suppresses the expression of these genes. IMPLICATIONS: Our studies identified the SOX9 protein as a "master regulator" of breast cancer cell survival and metastasis, and provide preclinical rationale to develop SOX9 inhibitors for the treatment of women with metastatic triple-negative breast cancer.

PI4KIIIß is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIß (PI4KIIIß). Molecular, biochemical, and cell biological studies show that PI4KIIIß-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIß-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIß antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIß-dependent secretion for cancer cell survival and tumor progression.

Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1.

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and is associated with a poor prognosis due to frequent distant metastasis and lack of effective targeted therapies. Previously, we identified maternal embryonic leucine zipper kinase (MELK) to be highly expressed in TNBCs as compared with ER-positive breast cancers. Here we determined the molecular mechanism by which MELK is overexpressed in TNBCs. Analysis of publicly available data sets revealed that MELK mRNA is elevated in p53-mutant breast cancers. Consistent with this observation, MELK protein levels are higher in p53-mutant vs. p53 wild-type breast cancer cells. Furthermore, inactivation of wild-type p53, by loss or mutation of the p53 gene, increases MELK expression, whereas overexpression of wild-type p53 in p53-null cells reduces MELK promoter activity and MELK expression. We further analyzed MELK expression in breast cancer data sets and compared that with known wild-type p53 target genes. This analysis revealed that MELK expression strongly correlates with genes known to be suppressed by wild-type p53. Promoter deletion studies identified a p53-responsive region within the MELK promoter that did not map to the p53 consensus response elements, but to a region containing a FOXM1-binding site. Consistent with this result, knockdown of FOXM1 reduced MELK expression in p53-mutant TNBC cells and expression of wild-type p53 reduced FOXM1 expression. ChIP assays demonstrated that expression of wild-type p53 reduces binding of E2F1 (a critical transcription factor controlling FOXM1 expression) to the FOXM1 promoter, thereby, reducing FOXM1 expression. These results show that wild-type p53 suppresses FOXM1 expression, and thus MELK expression, through indirect mechanisms. Overall, these studies demonstrate that wild-type p53 represses MELK expression by inhibiting E2F1A-dependent transcription of FOXM1 and that mutation-driven loss of wild-type p53, which frequently occurs in TNBCs, induces MELK expression by suppressing FOXM1 expression and activity in p53-mutant breast cancers.

Potential risk of organophosphate exposure in male reproductive system of a non-target insect model Drosophila melanogaster.

Based on several adverse reports of pesticides on reproductive efficiency of various organisms, studies on "reproductive toxicity" have gained importance. Fecundity, reflecting reproductive success of any organism, is governed by several factors from female and male reproductive systems. This present study explored morphological and biochemical alterations in the male reproductive system of a non-target model organism, Drosophila melanogaster following chronic sub-lethal exposure (1st instar larvae differentially exposed to 1-6 µg/mL until adulthood) to the organophosphate (OP) pesticide, acephate (chronic LC50 8.71 µg/mL). This study demonstrates altered testis structure, decreased germ cell viability and gross body weight, increased activities of oxidative stress marker lipid peroxidase (LPO), and the endogenous antioxidant enzyme catalase (CAT)in addition with altered expression of reproductive marker proteins like vitellogenin and mitoferrin in acephate-exposed flies when compared to control counterparts. Altered reproductive behavior, indicated by a significant decline in the number of mating pairs, validates the adverse effect of chronic acephate exposure on male reproduction in the non-target insect model D. melanogaster.

The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression.

Estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple negative," breast cancer (TNBC) is a poor prognosis clinical subtype that occurs more frequently in younger women and is commonly treated with toxic chemotherapy. Effective targeted therapy for TNBC is urgently needed. Our previous studies have identified several kinases critical for TNBC growth. Since phosphatases regulate the function of kinase signaling pathways, we sought to identify critical growth-regulatory phosphatases that are expressed differentially in ER-negative, as compared to ER-positive, breast cancers. In this study, we examined the role of one of these differentially expressed phosphatases, the protein phosphatase Mg + 2/Mn + 2 dependent 1A (PPM1A) which is underexpressed in ER-negative breast cancer as compared to ER-positive breast cancers, in regulating TNBC growth. We found that PPM1A is deleted in ~40% of ER-negative breast cancers, and that induced expression of PPM1A suppresses in vitro and in vivo growth of TNBC cells. This study demonstrates that induction of PPM1A expression blocks the cell cycle and reduces CDK and Rb phosphorylation. These results suggest PPM1A is a crucial regulator of cell cycle progression in triple negative breast cancer. Our results also suggest that PPM1A loss should be explored as a predictive biomarker of CDK inhibitor sensitivity.

Virulence assay and role of Bacillus thuringiensis TS110 as biocontrol agent against the larval stages of rice leaffolder Cnaphalocrocis medinalis.

The bacterial isolate Bacillus thuringiensis TS110 was isolated from the rice field soil of Burdwan district, West Bengal, India. Bioassay test of the bacteria TS110 against 3rd, 4th and 5th instar larvae of Cnaphalocrocis medinalis was carried out. Cut leaf assay, potted plant assay and field assay were done. During filed assay, it has been observed that the LC50 (×107) values of TS110 against 3rd, 4th and 5th instar larvae of C. medinalis were 3.77, 5.29, 4.83 and 4.93, 4.42, 4.72 in dry and wet season, respectively. The morphological, biochemical and phylogenetic analysis of the isolate TS110 were done. TS110 was positive for catalase, nitrate reductase, methyl red, voges-proskauer, oxidase, urease, indole, citrate utilization, arginine dihydrolase test, starch, lipid, gelatin, casein, and lecithin hydrolysis test. TS110 showed fermentation test positive for glucose, fructose, mannose, arabinose and trehalose in nutrient broth medium. The antibiotic sensitivity test showed that the bacterial isolate was sensitive to kanamycin (30 µg/disc), nalidixic acid (30 µg/disc), rifampicin (5 µg/disc), doxycycline (30 µg/disc), gatifloxacin (10 µg/disc), vancomycin (30 µg/disc), gentamycin (10 µg/disc), ampicillin (10 µg/disc), ofloxacin (5 µg/disc), levofloxacin (5 µg/disc), streptomycin (10 µg/disc), gentamycin (10 µg/disc). The phylogenetic analysis revealed that TS110 was closely related to different species of B. thuringiensis submitted to the GenBank. On the basis of morpho-physiological and molecular characterization, the bacterial isolate was identified as B. thuringiensis.

Molecularly targeted therapies for p53-mutant cancers.

The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.